Benzamides and related inhibitors of factor xa

ABSTRACT

Novel benzamide compounds including their pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives having activity against mammalian factor Xa are described. Compositions containing such compounds are also described. The compounds and compositions are useful in vitro or in vivo for preventing or treating coagulation disorders.

FIELD OF THE INVENTION

This invention relates to novel compounds which are potent and highlyselective inhibitors of isolated factor Xa or when assembled in theprothrombinase complex. These compounds show selectivity for factor Xaversus other proteases of the coagulation (e.g. thrombin, fVIIa, fIXa)or the fibrinolytic cascades (e.g. plasminogen activators, plasmin). Inanother aspect, the present invention relates to novelmonoamidino-containing compounds, their pharmaceutically acceptablesalts, and pharmaceutically acceptable compositions thereof which areuseful as potent and specific inhibitors of blood coagulation inmammals. In yet another aspect, the invention relates to methods forusing these inhibitors as therapeutic agents for disease states inmammals characterized by coagulation disorders.

BACKGROUND OF THE INVENTION

Hemostasis, the control of bleeding, occurs by surgical means, or by thephysiological properties of vasoconstriction and coagulation. Thisinvention is particularly concerned with blood coagulation and ways inwhich it assists in maintaining the integrity of mammalian circulationafter injury, inflammation, disease, congenital defect, dysfunction orother disruption. Although platelets and blood coagulation are bothinvolved in thrombus formation, certain components of the coagulationcascade are primarily responsible for the amplification or accelerationof the processes involved in platelet aggregation and fibrin deposition.

Thrombin is a key enzyme in the coagulation cascade as well as inhemostasis. Thrombin plays a central role in thrombosis through itsability to catalyze the conversion of fibrinogen into fibrin and throughits potent platelet activation activity. Direct or indirect inhibitionof thrombin activity has been the focus of a variety of recentanticoagulant strategies as reviewed by Claeson, G., “Synthetic Peptidesand Peptidomimetics as Substrates and Inhibitors of Thrombin and OtherProteases in the Blood Coagulation System”, Blood Coag. Fibrinol. 5,411-436 (1994). Several classes of anticoagulants currently used in theclinic directly or indirectly affect thrombin (i.e. heparins,low-molecular weight heparins, heparin-like compounds and coumarins).

A prothrombinase complex, including Factor Xa (a serine protease, theactivated form of its Factor X precursor and a member of the calcium ionbinding, gamma carboxyglutamyl (Gla)-containing, vitamin K dependent,blood coagulation glycoprotein family), converts the zymogen prothrombininto the active procoagulant thrombin. Unlike thrombin, which acts on avariety of protein substrates as well as at a specific receptor, factorXa appears to have a single physiologic substrate, namely prothrombin.Since one molecule of factor Xa may be able to generate up to 138molecules of thrombin (Elodi et al., Thromb. Res. 15, 617-619 (1979)),direct inhibition of factor Xa as a way of indirectly inhibiting theformation of thrombin may be an efficient anticoagulant strategy.Therefore, it has been suggested that compounds which selectivelyinhibit factor Xa may be useful as in vitro diagnostic agents, or fortherapeutic administration in certain thrombotic disorders, see e.g., WO94/13693.

Polypeptides derived from hematophagous organisms have been reportedwhich are highly potent and specific inhibitors of factor Xa. U.S. Pat.No. 4,588,587 describes anticoagulant activity in the saliva of theMexican leech, Haementeria officinalis. A principal component of thissaliva was shown to be the polypeptide factor Xa inhibitor, antistasin(ATS), by Nutt, E. et al., “The Amino Acid Sequence of Antistasin, aPotent Inhibitor of Factor Xa Reveals a Repeated Internal Structure”, J.Biol. Chem., 263, 10162-10167 (1988). Another potent and highly specificinhibitor of Factor Xa, called tick anticoagulant peptide (TAP), hasbeen isolated from the whole body extract of the soft tick Ornithidorosmoubata, as reported by Waxman, L., et al., “Tick Anticoagulant Peptide(TAP) is a Novel Inhibitor of Blood Coagulation Factor Xa” Science, 248,593-596 (1990).

Factor Xa inhibitory compounds which are not large polypeptide-typeinhibitors have also been reported including: Tidwell, R. R. et al.,“Strategies for Anticoagulation With Synthetic Protease Inhibitors. XaInhibitors Versus Thrombin Inhibitors”, Thromb. Res., 19, 339-349(1980); Turner, A. D. et al., “p-Amidino Esters as IrreversibleInhibitors of Factor IXa and Xa and Thrombin”, Biochemistry, 25,4929-4935 (1986); Hitomi, Y. et al., “Inhibitory Effect of New SyntheticProtease Inhibitor (FUT-175) on the Coagulation System”, Haemostasis,15, 164-168 (1985); Sturzebecher, J. et al., “Synthetic Inhibitors ofBovine Factor Xa and Thrombin. Comparison of Their AnticoagulantEfficiency”, Thromb. Res., 54, 245-252 (1989); Kam, C. M. et al.,“Mechanism Based Isocoumarin Inhibitors for Trypsin and BloodCoagulation Serine Proteases: New Anticoagulants”, Biochemistry, 27,2547-2557 (1988); Hauptmann, J. et al., “Comparison of the Anticoagulantand Antithrombotic Effects of Synthetic Thrombin and Factor XaInhibitors”, Thromb. Haemost., 63, 220-223 (1990); and the like.

Others have reported Factor Xa inhibitors which are small moleculeorganic compounds, such as nitrogen containing heterocyclic compoundswhich have amidino substituent groups, wherein two functional groups ofthe compounds can bind to Factor Xa at two of its active sites. Forexample, WO 98/28269 describes pyrazole compounds having a terminalC(═NH)—NH₂ group; WO 97/21437 describes benzimidazole compoundssubstituted by a basic radical which are connected to a naphthyl groupvia a straight or branched chain alkylene, —C(═O) or —S(═O)₂ bridginggroup; WO 99/10316 describes compounds having a4-phenyl-N-alkylamidino-piperidine and4-phenoxy-N-alkylamidino-piperidine group connected to a 3-amidinophenylgroup via a carboxamidealkyleneamino bridge; and EP 798295 describescompounds having a 4-phenoxy-N-alkylamidino-piperidine group connectedto an amidinonaphthyl group via a substituted or unsubstitutedsulfonamide or carboxamide bridging group.

There exists a need for effective therapeutic agents for the regulationof hemostasis, and for the prevention and treatment of thrombusformation and other pathological processes in the vasculature induced bythrombin such as restenosis and inflammation. In particular, therecontinues to be a need for compounds which selectively inhibit factor Xaor its precursors. Compounds that have different combinations ofbridging groups and functional groups than compounds previouslydiscovered are needed, particularly compounds which selectively orpreferentially bind to Factor Xa. Compounds with a higher degree ofbinding to Factor Xa than to thrombin are desired, especially thosecompounds having good bioavailability and/or solubility.

SUMMARY OF THE INVENTION

As discussed above, a number of non-peptide, specific, factor Xainhibitors have been described either in the scientific or patentliterature (Zhu and Scarborough, Ann Rep. Med. Chem. 35: 83-102 (2000)).Most of these compounds rely on the interaction of P1 and P4 elements ofthe inhibitor compounds with the S1 and S4 sub-sites on the factor Xaenzyme. In general, it has been described that P1 elements utilize ahighly charged benzamidine functionality in order to interact with theS1 pocket of the factor Xa enzyme. Furthermore, substitution on thebenzamidine nitrogens either by alkylation or cyclization (cyclicamidines) of these previously described inhibitors is detrimental totheir interaction with the enzyme at the S1 pocket. In the presentapplication, a novel series of inhibitors of factor Xa which do notutilize a S1-interacting benzamidine but utilize a neutral P1 speciesare described. In addition the compounds also utilize a substitutedbenzamidine or a cyclic amidine as a P4 element which can each interactwith the S4 sub-site of factor Xa enzyme. Surprisingly, the inhibitorsof this invention with modified amidine elements are not only of highpotency in vitro, but also have excellent pharmacological andpharmaceutical properties in vivo. These are results that would not havebeen predicted for such structures.

Accordingly, the present invention relates to novel compounds whichinhibit factor Xa, their pharmaceutically acceptable isomers, salts,hydrates, solvates and prodrug derivatives, and pharmaceuticallyacceptable compositions thereof which have particular biologicalproperties and are useful as potent and specific inhibitors of bloodcoagulation in mammals. In another aspect, the invention relates tomethods of using these inhibitors as diagnostic reagents or astherapeutic agents for disease states in mammals characterized byundesired thrombosis or which have coagulation disorders, such as in thetreatment or prevention of any thrombotically mediated acute coronary orcerebrovascular syndrome, any thrombotic syndrome occurring in thevenous system, any coagulopathy, and any thrombotic complicationsassociated with extracorporeal circulation or instrumentation, and forthe inhibition of coagulation in biological samples.

In certain embodiments, this invention relates to novel compounds whichare potent and highly selective inhibitors of isolated factor Xa whenassembled in the prothrombinase complex. These compounds showselectivity for factor Xa versus other proteases of the coagulationcascade (e.g. thrombin, etc.) or the fibrinolytic cascade, and areuseful as diagnostic reagents as well as antithrombotic agents.

In one embodiment, the present invention relates to a compound accordingto the formula (I):

A-Q-D-E-G-J-X  (I)

where:A is selected from:

-   -   (a) C₁-C₆-alkyl;    -   (b) C₃-C₈-cycloalkyl;    -   (c) —N(R¹,R²), N(R¹,R²)—C(═NR³)—, N(R¹,R²)—C(═NR³)—N(R⁴)—,        R¹—C(═NR³)—, R¹—C(═NR³)—N(R⁴)—;    -   (d) phenyl, which is independently substituted with 0-2 R        substitutuents;    -   (e) naphthyl, which is independently substituted with 0-2 R        substitutuents; and    -   (f) a monocyclic or fused bicyclic heterocyclic ring system        having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the        ring system are selected from N, O and S, and wherein the ring        system may be substituted with 0-2 R substitutuents;        R is selected from:    -   H, halo, —CN, —CO₂R¹, —C(═O)—N(R¹,R²), —(CH₂)_(m)—CO₂R¹,        —(CH₂)_(m)—, C(═O)—N(R¹,R²), —NO₂, —SO₂N(R¹,R²), —SO₂R¹,        —(CH₂)_(m)NR¹R², —(CH₂)_(m)—C(═NR³)—R¹,        —(CH₂)_(m)C(═NR³)—N(R¹,R²), —(CH₂)_(m)—N(R⁴)—C(═NR³)—N(R¹,R²),        —(CH₂)_(m)NR¹— group appended to a 3 to 6 membered heterocyclic        ring containing from 1-4 heteroatoms selected from N, O and S,        C₁₋₄alkyl, C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl, —CF₃, —OR², and a 5-6 membered        heterocyclic system containing from 1-4 heteroatoms selected        from N, O and S, wherein from 1-4 hydrogen atoms on the        heterocyclic system may be independently replaced with a member        selected from the group consisting of halo, —C₁-C₄-alkyl,        C₁₋₄alkyl CN, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;        m is an integer of 0-2;        R¹,R²,R³ and R⁴ are independently selected from the group        consisting of:    -   H, —OR⁵, —N(—R⁵, —R⁶), —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,        —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —C₀₋₄alkylphenyl and        —C₀₋₄alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring        atoms of the phenyl and naphthyl moieties may be independently        replaced with a member selected from the group consisting of        halo, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl, —CN, and —NO₂; or    -   R¹ and R², or R² and R³ taken together can form a 3-8 membered        cycloalkyl or a heterocyclic ring system, wherein the        heterocyclic ring system may have from 3 to 10 ring atoms, with        1 to 2 rings being in the ring system and contain from 1-4        heteroatoms selected from N, O and S, wherein from 1-4 hydrogen        atoms on the heterocyclic ring system may be independently        replaced with a member selected from the group consisting of        halo, C₁-C₄-alkyl, —CN—C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,        —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;        R⁵ and R⁶ are independently selected from the group consisting        of:    -   H, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl, —C₀₋₄alkylphenyl and        —C₀₋₄alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring        atoms of the phenyl and naphthyl moieties may be independently        replaced with a member selected from the group consisting of        halo, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl, —CN, and —NO₂; or    -   R⁵ and R⁶ taken together can form a 3-8 membered cycloalkyl or a        heterocyclic ring system, wherein the heterocyclic ring system        may have from 3 to 10 ring atoms, with 1 to 2 rings being in the        ring system and contain from 1-4 heteroatoms selected from N, O        and S, wherein from 1-4 hydrogen atoms on the heterocyclic ring        system may be independently replaced with a member selected from        the group consisting of halo, —C₁-C₄-alkyl, —CN—C₁₋₄alkyl,        —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;        Q is a member selected from the group consisting of:    -   a direct link, —CH₂—, —C(═O)—, —O—, —N(R⁷)—, —N(R⁷)CH₂—,        —CH₂N(R⁷)—, —C(═NR⁷)—, —C(═O)—N(R⁷)—, —N(R⁷)—C(═O)—, —S—, —SO—,        —SO₂—, —SO₂—N(R⁷)— and —N(R⁷)—SO₂—;        R⁷ is selected from:    -   H, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl, —C₀₋₄alkylphenyl and        —C₀₋₄alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring        atoms of the phenyl and naphthyl moieties may be independently        replaced with a member selected from the group consisting of        halo, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl, —CN, and —NO₂;        D is a direct link or is a member selected from the group        consisting of:    -   (a) phenyl, which is independently substituted with 0-2 R^(1a)        substitutuents;    -   (b) naphthyl, which is independently substituted with 0-2 R^(1a)        substitutuents; and    -   (c) a monocyclic or fused bicyclic heterocyclic ring system        having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the        ring system are selected from N, O and S, and wherein the ring        system may be substituted from 0-2 R^(1a) substitutuents;        R^(1a) is selected from:    -   halo, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl, —CN, —NO₂, —(CH₂)_(n)NR^(2a)R^(3a),        —(CH₂)_(n)CO₂R^(2a), —(CH₂)_(n)CONR^(2a)R^(3a),        —SO₂NR^(2a)R^(3a), —SO₂R^(2a), —CF₃, —OR^(2a), and a 5-6        membered aromatic heterocyclic system containing from 1-4        heteroatoms selected from N, O and S, wherein from 1-4 hydrogen        atoms on the aromatic heterocyclic system may be independently        replaced with a member selected from the group consisting of        halo, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl, —CN and —NO₂;        R^(2a) and R^(3a) are independently selected from the group        consisting of:    -   H, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl, —C₀₋₄alkylphenyl and        —C₀₋₄alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring        atoms of the phenyl and naphthyl moieties may be independently        replaced with a member selected from the group consisting of        halo, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl, —CN and —NO₂;        n is an integer of 0-2;        E is a direct link or a member selected from the group        consisting of:    -   —C₁₋₂-alkyl-, —O—, —S—, —SO—, —SO₂—, —C₀₋₁-alkyl-C(═O),        —C₀₋₄-alkyl-C(═O)—N(—R⁸)—C₀₋₁-alkyl-,        —C₀₋₁-alkyl-N(—R⁸)—C(═O)—C₀₋₁-alkyl-, —N(—R⁸)—C(═O)—N(—R⁸)— and        —C₀₋₁-alkyl-N(—R⁸)—;        R⁸ is a member selected from the group consisting of:    -   H; —C₁₋₄-alkyl; —C₀₋₄-alkylaryl; —C₀₋₄-alkyl-heteroaryl;        —C₁₋₄-alkyl-C(═O)—OH, —C₁₋₄-alkyl-C(═O)—O—C₁₋₄-alkyl, and        —C₁₋₄-alkyl-C(═O)—N(—R^(2b), —R^(3b));        R^(2b) and R^(3b) are each a member independently selected from        the group consisting of:    -   H, —C₁₋₄-alkyl, —C₀₋₄-alkyl-aryl; —C₀₋₄-alkyl-heterocyclic        group, and R^(2b) and R^(3b) together with the N atom to which        they are attached can form a 5-8 membered heterocyclic ring        containing 1-4 heteroatoms selected from N, O and S, wherein the        heterocyclic ring may be substituted with 0-2 R^(1c) groups;        R^(1c) is a member selected from the group consisting of:    -   Halo; —C₁₋₄-alkyl; —CN, —NO₂; —C(═O)—N(—R^(2c), —R^(3c));        —C(═O)—OR^(2c); —(CH₂)_(q)—N(—R^(2c), —R^(3c)); —SO₂—N(—R^(2c),        —R^(3c)); —SO₂R^(2c); —CF₃ and —(CH₂)_(q)—OR^(2c);        R^(2c) and R^(3c) are each independently a member selected from        the group consisting of:    -   H; —C₁₋₄-alkyl and —C₁₋₄-alkyl-aryl;        q is an integer of 0-2;        G is a member selected from the group consisting of:    -   (a) C₂-alkenyl or C₃₋₈-cycloalkenyl, wherein the alkenyl and        cycloalkenyl attachment points are the alkenyl carbon atoms and        wherein the —C₂-alkenyl or —C₃₋₈-cycloalkenyl are substituted        with 0-4 R^(1d) groups;    -   (b) a phenylene group wherein the ring carbon atoms of the        phenylene group are substituted with 0-4 R^(1d) groups;    -   (c) a 3-8 membered a saturated, partially unsaturated or        aromatic monocyclic-heterocyclic ring system containing 1-4        heteroatoms selected from N, O and S, wherein 0-2 ring atoms of        the heterocyclic ring may be substituted with 0-4 R^(1d) groups;        and,    -   (d) an 8-10 membered fused heterocyclic bicyclic ring system,        containing 1-4 heteroatoms selected from N, O and S, wherein 0-2        ring atoms of the fused bicyclic ring system may be substituted        with 0-4 R^(1d) groups;        R^(1d) is a member selected from the group consisting of:    -   H, halo; C₁₋₆-alkyl, carbocylic aryl, —CN; —NO₂;        —(CH₂)₀₋₆—NR^(2d)R^(3d); —SO₂NR^(2d)R^(3d); —SO₂R^(2d); —CF₃;        —(CH₂)₀₋₆—OR^(2d); —OH, —OC₁₋₆alkyl, —O—(CH₂)₁₋₆OR^(2d);        —O—(CH₂)₁₋₆—C(═O)—O—R^(2d); —O—(CH₂)₁₋₆—C(═O)—N(R^(2d),R^(3d));        —N(R^(5a))—(CH₂)₁₋₆—OR^(2d);        —N(R^(5a))—(CH₂)₁₋₆—N(R^(2d),R^(3d)); —C(═O)—N(R^(2d),R^(3d));        —N(R^(5a))—(CH₂)₁₋₆—C(═O)—N(R^(2d),R^(3d));        —N(—(CH₂)₁₋₆—OR^(2d))₂; —N(R^(5a))—(CH₂)₁₋₆—OR^(2d);        —N(R^(5a))—C(═O)—R^(2d); —N(R^(5a))—SO₂—R^(2d);        —(CH₂)₀₋₆—C(═O)—O—R^(2d); —(CH₂)₀₋₆—C(═O)—N(R^(2d),R^(3d));        —(CH₂)₀₋₆—C(═NR^(2d))—N(R^(3d),R^(4d));        —(CH₂)₀₋₆—N(R^(5a))C(═NR^(2d))—N(R^(3d),R^(4d)); a        —(CH₂)₀₋₆—N(R^(3d))C₅₋₆ membered saturated, partially        unsaturated or aromatic heterocyclic ring containing 1-4        heteroatoms selected from N, O and S, and a —(CH₂)₀₋₆-5-6        membered saturated, partially unsaturated or aromatic        heterocyclic ring containing 1-4 heteroatoms selected from N, O        and S;        R^(5a),R^(2d),R^(3d) and R^(4d) are each independently a member        selected from the group consisting of:    -   H, C₁₋₆-alkyl and C₁₋₆-alkylaryl, —CN; —NO₂; carbocylic aryl,        —CN; —NO₂; or    -   R^(2d) and R^(3d) taken together with the N atoms they are        independently attached form a 5-7 membered saturated, partially        unsaturated or aromatic heterocyclic ring; or    -   R^(3d) and R^(4d) taken together with the N atom to which they        are attached form a 5-8 membered saturated, partially        unsaturated or aromatic heterocyclic ring containing 1-4        heteroatoms selected from N, O and S;        J is a direct link or is a member selected from the group        consisting of:    -   —N(—R⁹)—C(═O)—; —C(═O)—N(—R⁹)—; —O—; —S—; —SO—; —SO₂—; —CH₂—;        —N(—R⁹)—; and —N(—R⁹)—SO₂—;        R⁹ is a member selected from the group consisting of:    -   H; —C₁₋₄-alkyl-carbocyclic aryl; —(CH₂)₀₋₄-5-6 membered        saturated, partially unsaturated or aromatic heterocyclic ring        containing 1-4 heteroatoms selected from N, O and S;        —(CH₂)₁₋₆—C(═O)—O—C₁₋₄-alkyl; and        —(CH₂)₁₋₆—C(═O)—N(R^(6a),R^(6b));        R^(6a) and R^(6b) are each a member independently selected from        the group consisting of:    -   H and —C₁₋₆-alkyl;        X is a member selected from the group consisting of:    -   (a) phenyl substituted with 0-3 R^(1e) groups;    -   (b) naphthyl substituted with 0-3 R^(1e) groups and    -   (c) a 6-membered aromatic heterocyclic ring system containing        1-3 N atoms and having 0-3 ring atoms substituted with 0-3        R^(1e) groups; and    -   (d) an 8-10 membered fused aromatic heterocyclic bicyclic ring        system containing 1-4 heteroatoms selected from N, O and S and        0-3 ring atoms of the fused heterocyclic bicyclic ring system        are substituted with 0-3 R^(1e) groups;        R^(1e) is a member independently selected from the group        consisting of:    -   Halo; CF₃; —C₁₋₄-alkyl; carbocyclic aryl; —C₀₋₂-alkyl-CN;        —O—R^(2e); —C₀₋₂-alkyl-C(═O)—O—R^(2e);        —C₀₋₂-alkyl-C(═O)—N(R^(2e),R^(3e)); —C₀₋₂-alkyl-NO₂;        —C₀₋₂-alkyl-N(R^(2e),R^(3e)); —C₀₋₂-alkyl-SO₂—N(R^(2e),R^(3e));        —C₀₋₂-alkyl-SO₂—R^(2e); trihaloalkyl; —O—C₀₋₂-alkyl-O—R^(2e);        —C₀₋₂-alkyl-O—R^(2e); —O—C₁₋₄-alkyl-C(═O)—N(R^(2e),R^(3e));        —O—C₁₋₄-alkyl-C(═O)—O—R^(2e);        —C₀₋₂-alkyl-N(R^(2e))—C(═O)—R^(3e);        —C₀₋₂-alkyl-N(—R^(2e))—SO₂—R^(3e); —CH₂—N(R^(2e))—C(═O)—R^(3e);        —CH₂—N(R^(2e))—SO₂—R^(3e); —(CH₂)₀₋₆—NR^(2e)R^(3e);        —C(═O)—N(R^(2e),R^(3e)); —N(—(CH₂)₁₋₆—OR^(2e))₂;        —N(R¹⁰)—(CH₂)₁₋₆—OR^(2e); —N(R¹⁰)—C(═O)—R^(2e);        —N(R¹⁰)—SO₂—R^(2e); —C(N(R¹⁰))—N(R^(2e),R^(3e)); and a        —(CH₂)₀₋₆-5-6 membered saturated, partially unsaturated or        aromatic heterocyclic ring containing 1-4 heteroatoms selected        from N, O and S;        R¹⁰,R^(2e) and R^(3e) are each independently a member selected        from the group consisting of:    -   H; —C₁₋₄-alkyl; —C₀₋₂-alkyl-O—R^(1g); —C₀₋₂-alkyl-N(—R^(1g),        —R^(2g)); —C₁₋₄-alkyl-carbocyclic aryl;        —C₁₋₄-alkyl-heterocyclic; and R¹⁰ and R^(2e), or R^(2e) and        R^(3e) together with the N atom to which they are attached can        form 5-8 membered heterocyclic ring containing 1-4 heteroatoms        selected from N, O and S which can be substituted with 0-2        R^(1g) groups;        R^(1g) and R^(2g) are independently a member selected from the        group of:    -   H; halo; —C₁₋₄-alkyl, a carbocyclic aryl group; a saturated,        partially unsaturated or aromatic heterocyclic group; —CN;        —C(═O)—N(R^(3g))R^(4g); —C(═O)—OR^(3g); —NO₂;        —(CH₂)_(p)—NR^(3g)R^(4g); —SO₂NR^(3g)R^(4g); —SO₂R^(3g); —CF₃;        and —(CH₂)_(p)OR^(3g);        p is an integer of 0-2;        R^(3g) and R^(49g) are each independently selected from the        group consisting of:    -   H; C₁₋₄-alkyl and —C₀₋₄-alkyl-carbocyclic aryl;

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

In certain aspects of this invention, compounds are provided which areuseful as diagnostic reagents. In another aspect, the present inventionincludes pharmaceutical compositions comprising a pharmaceuticallyeffective amount of the compounds of this invention and apharmaceutically acceptable carrier. In yet another aspect, the presentinvention includes methods comprising using the above compounds andpharmaceutical compositions for preventing or treating disease statescharacterized by undesired thrombosis or disorders of the bloodcoagulation process in mammals, or for preventing coagulation in storedblood products and samples. Optionally, the methods of this inventioncomprise administering the pharmaceutical composition in combinationwith an additional therapeutic agent such as an antithrombotic and/or athrombolytic agent and/or an anticoagulant.

DETAILED DESCRIPTION OF THE INVENTION Definitions

In accordance with the present invention and as used herein, thefollowing terms are defined with the following meanings, unlessexplicitly stated otherwise.

The term “alkenyl” refers to a trivalent straight chain or branchedchain unsaturated aliphatic radical. The term “alkinyl” (or “alkynyl”)refers to a straight or branched chain aliphatic radical that includesat least two carbons joined by a triple bond. If no number of carbons isspecified alkenyl and alkinyl each refer to radicals having from 2-12carbon atoms.

The term “alkyl” refers to saturated aliphatic groups includingstraight-chain, branched-chain and cyclic groups having the number ofcarbon atoms specified, or if no number is specified, having up to 12carbon atoms. The term “cycloalkyl” as used herein refers to a mono-,bi-, or tricyclic aliphatic ring having 3 to 14 carbon atoms andpreferably 3 to 7 carbon atoms.

As used herein, the terms “carbocyclic ring structure” and “C₃₋₁₆carbocyclic mono, bicyclic or tricyclic ring structure” or the like areeach intended to mean stable ring structures having only carbon atoms asring atoms wherein the ring structure is a substituted or unsubstitutedmember selected from the group consisting of: a stable monocyclic ringwhich is aromatic ring (“aryl”) having six ring atoms; a stablemonocyclic non-aromatic ring having from 3 to 7 ring atoms in the ring;a stable bicyclic ring structure having a total of from 7 to 12 ringatoms in the two rings wherein the bicyclic ring structure is selectedfrom the group consisting of ring structures in which both of the ringsare aromatic, ring structures in which one of the rings is aromatic andring structures in which both of the rings are non-aromatic; and astable tricyclic ring structure having a total of from 10 to 16 atoms inthe three rings wherein the tricyclic ring structure is selected fromthe group consisting of: ring structures in which three of the rings arearomatic, ring structures in which two of the rings are aromatic andring structures in which three of the rings are non-aromatic. In eachcase, the non-aromatic rings when present in the monocyclic, bicyclic ortricyclic ring structure may independently be saturated, partiallysaturated or fully saturated. Examples of such carbocyclic ringstructures include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane,[4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin),2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, ortetrahydronaphthyl (tetralin). Moreover, the ring structures describedherein may be attached to one or more indicated pendant groups via anycarbon atom which results in a stable structure. The term “substituted”as used in conjunction with carbocyclic ring structures means thathydrogen atoms attached to the ring carbon atoms of ring structuresdescribed herein may be substituted by one or more of the substituentsindicated for that structure if such substitution(s) would result in astable compound.

The term “aryl” which is included with the term “carbocyclic ringstructure” refers to an unsubstituted or substituted aromatic ring,substituted with one, two or three substituents selected fromloweralkoxy, loweralkyl, loweralkylamino, hydroxy, halogen, cyano,hydroxyl, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxyl,carboalkoxy and carboxamide, including but not limited to carbocyclicaryl, heterocyclic aryl, and biaryl groups and the like, all of whichmay be optionally substituted. Preferred aryl groups include phenyl,halophenyl, loweralkylphenyl, napthyl, biphenyl, phenanthrenyl andnaphthacenyl.

The term “arylalkyl” which is included with the term “carbocyclic aryl”refers to one, two, or three aryl groups having the number of carbonatoms designated, appended to an alkyl group having the number of carbonatoms designated. Suitable arylalkyl groups include, but are not limitedto, benzyl, picolyl, naphthylmethyl, phenethyl, benzyhydryl, trityl, andthe like, all of which may be optionally substituted.

As used herein, the term “heterocyclic ring” or “heterocyclic ringsystem” is intended to mean a substituted or unsubstituted memberselected from the group consisting of stable monocyclic ring having from5-7 members in the ring itself and having from 1 to 4 hetero ring atomsselected from the group consisting of N, O and S; a stable bicyclic ringstructure having a total of from 7 to 12 atoms in the two rings whereinat least one of the two rings has from 1 to 4 hetero atoms selected fromN, O and S, including bicyclic ring structures wherein any of thedescribed stable monocyclic heterocyclic rings is fused to a hexane orbenzene ring; and a stable tricyclic heterocyclic ring structure havinga total of from 10 to 16 atoms in the three rings wherein at least oneof the three rings has from 1 to 4 hetero atoms selected from the groupconsisting of N, O and S. Any nitrogen and sulfur atoms present in aheterocyclic ring of such a heterocyclic ring structure may be oxidized.Unless indicated otherwise the terms “heterocyclic ring” or“heterocyclic ring system” include aromatic rings, as well asnon-aromatic rings which can be saturated, partially saturated or fullysaturated non-aromatic rings. Also, unless indicated otherwise the term“heterocyclic ring system” includes ring structures wherein all of therings contain at least one hetero atom as well as structures having lessthan all of the rings in the ring structure containing at least onehetero atom, for example bicyclic ring structures wherein one ring is abenzene ring and one of the rings has one or more hetero atoms areincluded within the term “heterocyclic ring systems” as well as bicyclicring structures wherein each of the two rings has at least one heteroatom. Moreover, the ring structures described herein may be attached toone or more indicated pendant groups via any hetero atom or carbon atomwhich results in a stable structure. Further, the term “substituted”means that one or more of the hydrogen atoms on the ring carbon atom(s)or nitrogen atom(s) of the each of the rings in the ring structuresdescribed herein may be replaced by one or more of the indicatedsubstituents if such replacement(s) would result in a stable compound.Nitrogen atoms in a ring structure may be quaternized, but suchcompounds are specifically indicated or are included within the term “apharmaceutically acceptable salt” for a particular compound. When thetotal number of O and S atoms in a single heterocyclic ring is greaterthan 1, it is preferred that such atoms not be adjacent to one another.Preferably, there are no more that 1 O or S ring atoms in the same ringof a given heterocyclic ring structure.

Examples of monocylic and bicyclic heterocylic ring systems, inalphabetical order, are acridinyl, azocinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl,carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl,furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl(benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pryidooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl and xanthenyl. Preferred heterocyclic ring structuresinclude, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl,pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl,1H-indazolyl, oxazolinyl, or isatinoyl. Also included are fused ring andspiro compounds containing, for example, the above heterocylic ringstructures.

As used herein the term “aromatic heterocyclic ring system” hasessentially the same definition as for the monocyclic and bicyclic ringsystems except that at least one ring of the ring system is an aromaticheterocyclic ring or the bicyclic ring has an aromatic or non-aromaticheterocyclic ring fused to an aromatic carbocyclic ring structure.

The terms “halo” or “halogen” as used herein refer to Cl, Br, F or Isubstituents. The term “haloalkyl”, and the like, refer to an aliphaticcarbon radicals having at least one hydrogen atom replaced by a Cl, Br,F or I atom, including mixtures of different halo atoms. Trihaloalkylincludes trifluoromethyl and the like as preferred radicals, forexample.

The term “methylene” refers to —CH₂—.

The term “pharmaceutically acceptable salts” includes salts of compoundsderived from the combination of a compound and an organic or inorganicacid. These compounds are useful in both free base and salt form. Inpractice, the use of the salt form amounts to use of the base form; bothacid and base addition salts are within the scope of the presentinvention.

“Pharmaceutically acceptable acid addition salt” refers to saltsretaining the biological effectiveness and properties of the free basesand which are not biologically or otherwise undesirable, formed withinorganic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid and the like, and organic acids suchas acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalicacid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaricacid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicyclic acid and the like.

“Pharmaceutically acceptable base addition salts” include those derivedfrom inorganic bases such as sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum salts andthe like. Particularly preferred are the ammonium, potassium, sodium,calcium and magnesium salts. Salts derived from pharmaceuticallyacceptable organic nontoxic bases include salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperizine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly preferredorganic nontoxic bases are isopropylamine, diethylamine, ethanolamine,trimethamine, dicyclohexylamine, choline, and caffeine.

“Biological property” for the purposes herein means an in vivo effectoror antigenic function or activity that is directly or indirectlyperformed by a compound of this invention that are often shown by invitro assays. Effector functions include receptor or ligand binding, anyenzyme activity or enzyme modulatory activity, any carrier bindingactivity, any hormonal activity, any activity in promoting or inhibitingadhesion of cells to an extracellular matrix or cell surface molecules,or any structural role. Antigenic functions include possession of anepitope or antigenic site that is capable of reacting with antibodiesraised against it.

In the compounds of this invention, carbon atoms bonded to fournon-identical substituents are asymmetric. Accordingly, the compoundsmay exist as diastereoisomers, enantiomers or mixtures thereof. Thesyntheses described herein may employ racemates, enantiomers ordiastereomers as starting materials or intermediates. Diastereomericproducts resulting from such syntheses may be separated bychromatographic or crystallization methods, or by other methods known inthe art. Likewise, enantiomeric product mixtures may be separated usingthe same techniques or by other methods known in the art. Each of theasymmetric carbon atoms, when present in the compounds of thisinvention, may be in one of two configurations (R or S) and both arewithin the scope of the present invention.

PREFERRED EMBODIMENTS

The invention provides a compound according to the formula (I):

A-Q-D-E-G-J-X  (I)

where:A is selected from:

-   -   (a) C₁-C₆-alkyl;    -   (b) C₃-C₈-cycloalkyl;    -   (c) —N(R¹,R²), N(R¹,R²)—C(═NR³)—, N(R¹,R²)—C(═NR³)—N(R⁴)—,        R¹—C(═NR³)—, R¹—C(═NR³)—N(R⁴)—;    -   (d) phenyl, which is independently substituted with 0-2 R        substitutuents;    -   (e) naphthyl, which is independently substituted with 0-2 R        substitutuents; and    -   (f) a monocyclic or fused bicyclic heterocyclic ring system        having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the        ring system are selected from N, O and S, and wherein the ring        system may be substituted with 0-2 R substitutuents;        R is selected from:    -   H, halo, —CN, —CO₂R¹, —C(═O)—N(R¹,R²), —(CH₂)_(m)—CO₂R¹,        —(CH₂)_(m)—C(═O)—N(R¹,R²), —NO₂, —SO₂N(R¹,R²), —SO₂R¹,        —(CH₂)_(m)NR¹R², —(CH₂)_(m)—C(═NR³)—R¹,        —(CH₂)_(m)C(═NR³)—N(R¹,R²), —(CH₂)_(m)—N(R⁴)—C(═NR³)—N(R¹,R²),        —(CH₂)_(m)NR¹— C₃₋₆heterocyclics, C₁₋₄alkyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, —CF₃,        —OR², and a 5-6 membered heterocyclic system containing from 1-4        heteroatoms selected from N, O and S, wherein from 1-4 hydrogen        atoms on the heterocyclic system may be independently replaced        with a member selected from the group consisting of halo,        C₁-C₄-alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;        m is an integer of 0-2;        R¹,R²,R³ and R⁴ are independently selected from the group        consisting of:    -   H, —OR⁵, —N(—R⁵, —R⁶), —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,        —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —C₀₋₄alkylphenyl and        —C₀₋₄alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring        atoms of the phenyl and naphthyl moieties may be independently        replaced with a member selected from the group consisting of        halo, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl, —CN, and —NO₂; or    -   R¹ and R², or R² and R³ taken together can form a 3-8 membered        cycloalkyl or a heterocyclic ring system, wherein the        heterocyclic ring system may have from 3 to 10 ring atoms, with        1 to 2 rings being in the ring system and contain from 1-4        heteroatoms selected from N, O and S, wherein from 1-4 hydrogen        atoms on the heterocyclic ring system may be independently        replaced with a member selected from the group consisting of        halo, C₁-C₄-alkyl, —CN—C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,        —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;        R⁵ and R⁶ are independently selected from the group consisting        of:    -   H, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl, —C₀₋₄alkylphenyl and        —C₀₋₄alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring        atoms of the phenyl and naphthyl moieties may be independently        replaced with a member selected from the group consisting of        halo, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl, —CN, and —NO₂; or    -   R⁵ and R⁶ taken together can form a 3-8 membered cycloalkyl or a        heterocyclic ring system, wherein the heterocyclic ring system        may have from 3 to 10 ring atoms, with 1 to 2 rings being in the        ring system and contain from 1-4 heteroatoms selected from N, O        and S, wherein from 1-4 hydrogen atoms on the heterocyclic ring        system may be independently replaced with a member selected from        the group consisting of halo, C₁-C₄-alkyl, —CN—C₁₋₄alkyl,        —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;        Q is a member selected from the group consisting of:    -   a direct link, —CH₂—, —C(═O)—, —O—, —N(R⁷)—, —N(R⁷)CH₂—,        —CH₂N(R⁷)—, —C(═NR⁷)—, —C(═O)—N(R⁷)—, —N(R⁷)—C(═O)—, —S—, —SO—,        —SO₂—, —SO₂—N(R⁷)— and —N(R⁷)—SO₂—;        R⁷ is selected from:    -   H, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl, —C₀₋₄alkylphenyl and        —C₀₋₄alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring        atoms of the phenyl and naphthyl moieties may be independently        replaced with a member selected from the group consisting of        halo, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl, —CN, and —NO₂;        D is a direct link or is a member selected from the group        consisting of:    -   (a) phenyl, which is independently substituted with 0-2 R^(1a)        substitutuents;    -   (b) naphthyl, which is independently substituted with 0-2 R^(1a)        substitutuents; and    -   (c) a monocyclic or fused bicyclic heterocyclic ring system        having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the        ring system are selected from N, O and S, and wherein the ring        system may be substituted from 0-2 R^(1a) substitutuents;        R^(1a) is selected from:    -   halo, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl, —CN, —NO₂, —(CH₂)_(n)NR^(2a)R^(3a),        —(CH₂)_(n)CO₂R^(2a), —(CH₂)_(n)CONR^(2a)R^(3a),        —SO₂NR^(2a)R^(3a), —SO₂R^(2a), —CF₃, —OR^(2a), and a 5-6        membered aromatic heterocyclic system containing from 1-4        heteroatoms selected from N, O and S, wherein from 1-4 hydrogen        atoms on the aromatic heterocyclic system may be independently        replaced with a member selected from the group consisting of        halo, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl, —CN and —NO₂;        R^(2a) and R^(3a) are independently selected from the group        consisting of:    -   H, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl, —C₀₋₄alkylphenyl and        —C₀₋₄alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring        atoms of the phenyl and naphthyl moieties may be independently        replaced with a member selected from the group consisting of        halo, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl, —CN and —NO₂;        n is an integer of 0-2;        E is a direct link or a member selected from the group        consisting of:    -   —C₁₋₂-alkyl-, —O—, —S—, —SO—, —SO₂—, —C₀₋₁-alkyl-C(═O)—,        —C₀₋₁-alkyl-C(═O)—N(—R⁸)—C₀₋₁-alkyl-, —N(—R⁸)—C(═O)—N(—R⁸)— and        —C₀₋₁-alkyl-N(—R⁸)—;        R⁸ is a member selected from the group consisting of:    -   H; —C₁₋₄-alkyl; —C₀₋₄-alkylaryl; —C₀₋₄-alkyl-heteroaryl;        —C₁₋₄-alkyl-C(═O)—OH, —C₁₋₄-alkyl-C(═O)—O—C₁₋₄-alkyl, and        —C₁₋₄-alkyl-C(═O)—N(—R^(2b), —R^(3b));        R^(2b) and R^(3b) are each a member independently selected from        the group consisting of:    -   H, —C₁₋₄-alkyl, —C₀₋₄-alkyl-aryl; —C₀₋₄-alkyl-heterocyclic        group, and R^(2b) and R^(3b) together with the N atom to which        they are attached can form a 5-8 membered heterocyclic ring        containing 1-4 heteroatoms selected from N, O and S, wherein the        heterocyclic ring may be substituted with 0-2 R^(1c) groups;        R^(1c) is a member selected from the group consisting of:    -   Halo; —C₁₋₄-alkyl; —CN, —NO₂; —C(═O)—N(—R^(2c), —R^(3c));        —C(═O)—OR^(2c); —(CH₂)_(q)—N(—R^(2c), —R^(3c)); —SO₂—N(—R^(2c),        —R^(3c)); —SO₂R^(2c); —CF₃ and —(CH₂)_(q)—OR^(2c);        R^(2c) and R^(3c) are each independently a member selected from        the group consisting of:    -   H; —C₁₋₄-alkyl and —C₁₋₄-alkyl-aryl;        q is an integer of 0-2;        G is a member selected from the group consisting of:    -   (a) C₂-alkenyl or C₃₋₈-cycloalkenyl, wherein the alkenyl and        cycloalkenyl attachment points are the alkenyl carbon atoms and        wherein C₂-alkenyl or C₃₋₈-cycloalkenyl are substituted with 0-4        R^(1d) groups;    -   (b) a phenylene group wherein the ring carbon atoms of the        phenylene group are substituted with 0-4 R^(1d) groups;    -   (c) a 3-8 membered a saturated, partially unsaturated or        aromatic monocyclic-heterocyclic ring system containing 1-4        heteroatoms selected from N, O and S, wherein 0-4 ring atoms of        the heterocyclic ring may be substituted with 0-4 R^(1d) groups;        and,    -   (d) an 8-10 membered fused heterocyclic bicyclic ring system,        containing 1-4 heteroatoms selected from N, O and S, wherein 0-4        ring atoms of the fused bicyclic ring system may be substituted        with 0-4 R^(1d) groups;        R^(1d) is a member selected from the group consisting of:    -   H, halo; C₁₋₆-alkyl, carbocylic aryl, —CN; —NO₂;        —(CH₂)₀₋₆—NR^(2d)R^(3d); —SO₂NR^(2d)R^(3d); —SO₂R^(2d); —CF₃;        —(CH₂)₀₋₆—OR^(2d); —OH, —OC₁₋₆alkyl, —O—(CH₂)₁₋₆OR^(2d);        —O—(CH₂)₁₋₆—C(═O)—O—R^(2d); —O—(CH₂)₁₋₆—C(═O)—N(R^(2d),R^(3d));        —N(R^(5a))—(CH₂)₁₋₆—OR^(2d);        —N(R^(5a))—(CH₂)₁₋₆—N(R^(2d),R^(3d)); —C(═O)—N(R^(2d),R^(3d));        —N(R^(5a))—(CH₂)₁₋₆—C(═O)—N(R^(2d),R^(3d));        —N(—(CH₂)₁₋₆—OR^(2d))₂; —N(R^(5a))—(CH₂)₁₋₆—OR^(2d);        —N(R^(5a))—C(═O)—R^(2d); —N(R^(5a))—SO₂—R^(2d);        —(CH₂)₀₋₆—C(═O)—O—R^(2d); —(CH₂)₀₋₆—C(═O)—N(R^(2d),R^(3d));        —(CH₂)₀₋₆—C(═NR^(2d))—N(R^(3d),R^(4d));        —(CH₂)₀₋₆—N(R^(5a))C(═NR^(2d))—N(R^(3d),R^(4d)); and        —(CH₂)₀₋₆—N(—R^(3d))— group attached directly by its nitrogen        atom to a carbon atom of a 5 to 6 membered saturated, partially        unsaturated or aromatic heterocyclic ring containing 1-4        heteroatoms selected from N, O and S, and a —(CH₂)₀₋₆— group        attached to a 5-6 membered saturated, partially unsaturated or        aromatic heterocyclic ring containing 1-4 heteroatoms selected        from N, O and S;        R^(5a); R^(2d); R^(3d) and R^(4d) are each independently a        member selected from the group consisting of:    -   H, C₁₋₆-alkyl and C₁₋₆-alkylaryl, —CN; —NO₂; carbocylic aryl,        —CN; —NO₂; or    -   R^(2d) and R^(3d) taken together with the N atoms they are        independently attached form a 5-7 membered saturated, partially        unsaturated or aromatic heterocyclic ring; or    -   R^(3d) and R^(4d) taken together with the N atom to which they        are attached form a 5-8 membered saturated, partially        unsaturated or aromatic heterocyclic ring containing 1-4        heteroatoms selected from N, O and S;        J is a direct link or is a member selected from the group        consisting of:    -   —N(—R⁹)—C(═O)—; —C(═O)—N(—R⁹)—; —O—; —S—; —SO—; —SO₂—; —CH₂—;        —N(—R⁹)—; and —N(—R⁹)—SO₂—;        R⁹ is a member selected from the group consisting of:    -   H; —C₁₋₄-alkyl-carbocyclic aryl; —(CH₂)₀₋₄-5-6 membered        saturated, partially unsaturated or aromatic heterocyclic ring        containing 1-4 heteroatoms selected from N, O and S;        —(CH₂)₁₋₆—C(═O)—O—C₁₋₄-alkyl; and        —(CH₂)₁₋₆—C(═O)—N(R^(6a),R^(6b));        R^(6a) and R^(6b) are each a member independently selected from        the group consisting of:    -   H and —C₁₋₆-alkyl;        X is a member selected from the group consisting of:    -   (a) phenyl substituted with 0-3 R^(1e) groups;    -   (b) naphthyl substituted with 0-3 R^(1e) groups;    -   (c) a 6-membered aromatic heterocyclic ring system containing        1-3 N atoms and having 0-3 ring atoms substituted with 0-3        R^(1e) groups; and    -   (d) an 8-10 membered fused aromatic heterocyclic bicyclic ring        system containing 1-4 heteroatoms selected from N, O and S and        0-3 ring atoms of the fused heterocyclic bicyclic ring system        are substituted with 0-3 R^(1e) groups;        R^(1e) is a member independently selected from the group        consisting of:    -   Halo; CF₃; carbocyclic aryl; —C₀₋₂-alkyl-CN; —O—R^(2e);        —C₀₋₂-alkyl-C(═O)—O—R^(2e); —C₀₋₂-alkyl-C(═O)—N(R^(2e),R^(3e));        —C₀₋₂-alkyl-NO₂; —C₀₋₂-alkyl-N(R^(2e),R^(3e));        —C₀₋₂-alkyl-SO₂—N(R^(2e),R^(3e)); —C₀₋₂-alkyl-SO₂—R^(2e);        trihaloalkyl; —O—C₀₋₂-alkyl-O—R^(2e); —C₀₋₂-alkyl-O—R^(2e);        C(═O)—N(R^(2e),R^(3e)); —O—C₁₋₄-alkyl-C(═O)—O—R^(2e);        —C₀₋₂-alkyl-N(R^(2e))—C(═O)—R^(3e);        —C₀₋₂-alkyl-N(—R^(2e))—SO₂—R^(3e); —CH₂—N(R^(2e))—C(═O)—R^(3e);        —CH₂—N(R^(2e))—SO₂—R^(3e); —(CH₂)₀₋₆—NR^(2e)R^(3e);        —C(═O)—N(R^(2e),R^(3e)); —N(—(CH₂)₁₋₆—OR^(2e))₂;        —N(R¹⁰)—(CH₂)₁₋₆—OR^(2e); —N(R¹⁰)—C(═O)—R^(2e);        —N(R¹⁰)—SO₂—R^(2e); —C(═N(R¹⁰))—N(R^(2e),R^(3e)); and a        —(CH₂)₀₋₆-5-6 membered saturated, partially unsaturated or        aromatic heterocyclic ring containing 1-4 heteroatoms selected        from N, O and S;        R¹⁰,R^(2e) and R^(3e) are each independently a member selected        from the group consisting of:    -   H; —C₀₋₂-alkyl-O—R^(1g); —C₀₋₂-alkyl-N(—R^(1g), —R^(2g));        —C₁₋₄-alkyl-carbocyclic aryl; —C₁₋₄-alkyl-heterocyclic; and R¹⁰        and R^(2e), or R^(2e) and R^(3e) together with the N atom to        which they are attached can form 5-8 membered heterocyclic ring        containing 1-4 heteroatoms selected from N, O and S which can be        substituted with 0-2 R^(1g) groups;        R^(1g) and R^(2g) are independently a member selected from the        group of:    -   H; halo; —C₁₋₄-alkyl, a carbocyclic aryl group; a saturated,        partially unsaturated or aromatic heterocyclic group; —CN;        —C(═O)—N(R^(3g))R^(4g); —C(═O)—OR^(3g); —NO₂;        —(CH₂)_(p)—NR^(3g)R^(4g); —SO₂NR^(3g)R^(4g); —SO₂R^(3g); —CF₃;        and —(CH₂)_(p)OR^(3g);        p is an integer of 0-2; and        R^(3g) and leg are each independently selected from the group        consisting of:    -   H; C₁₋₄-alkyl and —C₀₋₄-alkyl-carbocyclic aryl;

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

A preferred embodiment of formula I are compounds of formula (Ia):

A-Q-D-E-G-J-X  (Ia)

where:A is selected from:

-   -   (a) C₁-C₆-alkyl;    -   (b) C₃-C₈-cycloalkyl;    -   (c) —N(R¹,R²), N(R¹,R²)—C(═NR³)—, N(R¹,R²)—C(═NR³)—N(R⁴)—,        R¹—C(═NR³)—, R¹—C(═NR³)—N(R⁴)—;    -   (d) phenyl, which is independently substituted with 0-2 R        substitutuents;    -   (e) naphthyl, which is independently substituted with 0-2 R        substitutuents; and    -   (f) monocyclic or fused bicyclic heterocyclic ring system having        from 5 to 10 ring atoms, wherein 1-4 ring atoms of the ring        system are selected from N, O and S, and wherein the ring system        may be substituted with 0-2 R substitutuents;        R is selected from:    -   H, halo, —CN, —CO₂R¹, —C(═O)—N(R¹,R²), —(CH₂)_(m)—CO₂R¹,        —(CH₂)_(m)—C(═O)—N(R¹,R²), —NO₂, —SO₂N(R¹,R²), —SO₂R¹,        —(CH₂)_(m)NR¹R², —(CH₂)_(m)—C(═NR³)—R¹,        —(CH₂)_(m)C(═NR³)—N(R¹,R²), —(CH₂)_(m)—N(R⁴)—C(═NR³)—N(R¹,R²),        —(CH₂)_(m)NR¹— group attached to a 3-6 membered heterocylic ring        having from 1 to 3 heteroatoms selected from the group        consisting of N, O and S, —C₂₋₆alkenyl, —C₂₋₆alkynyl,        —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —CF₃, —OR², and a 5-6        membered heterocyclic aromatic or partially saturated system,        including imidazoline, containing from 1-4 heteroatoms selected        from N, O and S, wherein from 1-4 hydrogen atoms on the        heterocyclic system may be independently replaced with a member        selected from the group consisting of halo, -methyl,        —C₂-C₄-alkyl, —CN, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;        m is an integer of 0-2;        R¹,R²,R³ and R⁴ are independently selected from the group        consisting of:    -   H, —OR⁵, —N(—R⁵, —R⁶), —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,        —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —C₀₋₄alkylphenyl and        —C₀₋₄alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring        atoms of the phenyl and naphthyl moieties may be independently        replaced with a member selected from the group consisting of        halo, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl, —CN, and —NO₂; or    -   R¹ and R², or R² and R³ taken together can form a 3-8 membered        cycloalkyl or a heterocyclic ring system, wherein the        heterocyclic ring system may have from 3 to 10 ring atoms, with        1 to 2 rings being in the ring system and contain from 1-4        heteroatoms selected from N, O and S, wherein from 1-4 hydrogen        atoms on the heterocyclic ring system may be independently        replaced with a member selected from the group consisting of        halo, C₁-C₄-alkyl, —CN—C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,        —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;        R⁵ and R⁶ are independently selected from the group consisting        of:    -   H, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl, —C₀₋₄alkylphenyl and        —C₀₋₄alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring        atoms of the phenyl and naphthyl moieties may be independently        replaced with a member selected from the group consisting of        halo, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl, —CN, and —NO₂; or    -   R⁵ and R⁶ taken together can form a 3-8 membered cycloalkyl or a        heterocyclic ring system, wherein the heterocyclic ring system        may have from 3 to 10 ring atoms, with 1 to 2 rings being in the        ring system and contain from 1-4 heteroatoms selected from N, O        and S, wherein from 1-4 hydrogen atoms on the heterocyclic ring        system may be independently replaced with a member selected from        the group consisting of halo, C₁-C₄-alkyl, —CN—C₁₋₄alkyl,        —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;        Q is a member selected from the group consisting of:    -   a direct link, —CH₂—, —C(═O)—, —O—, —NH—, —NMe-, —NHCH₂—,        —NMeCH₂—, —CH₂NH—, —C(═NH)—, —C(═O)—NH—, —NH—C(═O)—, —CH₂NMe-,        —C(═NMe)-;        D is a direct link or is a member selected from the group        consisting of:    -   (a) phenyl, which is independently substituted with 0-2 R^(1a)        substitutuents;    -   (b) naphthyl, which is independently substituted with 0-2 R^(1a)        substitutuents; and        -   a monocyclic or fused bicyclic heterocyclic ring system            having from 5 to 10 ring atoms, wherein 1-4 ring atoms of            the ring system are selected from N, O and S, and wherein            the ring system may be substituted from 0-2 R^(1a)            substitutuents;            R^(1a) is selected from:    -   halo, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl, —CN, —NO₂, —(CH₂)_(n)NR^(2a)R^(3a),        —(CH₂)_(n)CO₂R^(2a), —(CH₂)_(n)CONR^(2a)R^(3a),        —SO₂NR^(2a)R^(3a), —SO₂R^(2a), —CF₃, —OR^(2a), and a 5-6        membered aromatic heterocyclic system containing from 1-4        heteroatoms selected from N, O and S, wherein from 1-4 hydrogen        atoms on the aromatic heterocyclic system may be independently        replaced with a member selected from the group consisting of        halo, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl, —CN and —NO₂;        R^(2e) and R^(3a) are independently selected from the group        consisting of:    -   H, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl, —C₀₋₄alkylphenyl and        —C₀₋₄alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring        atoms of the phenyl and naphthyl moieties may be independently        replaced with a member selected from the group consisting of        halo, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl, —CN and —NO₂;        n is an integer of 0-2;        E is a member selected from the group consisting of:    -   a direct link, —O—, —NH—, —CH₂NH—, —NHCH₂—, —NMe-,        —NH—C(═O)—NH—, —C(═O)—NH—, —NH—C(═O)—;        G is a member selected from the group consisting of:    -   (a) a C₂-alkenyl group or a C₃₋₈-cycloalkenyl group, wherein the        alkenyl group and cycloalkenyl group attachment points are the        alkenyl carbon atoms and wherein the C₂-alkenyl group or        C₃₋₈-cycloalkenyl group is substituted with 0-4 R^(1d) groups;    -   (b) a phenylene group wherein the ring carbon atoms of the        phenylene group are substituted with 0-4 R^(1d) groups;    -   (c) a 3-8 membered a saturated, partially unsaturated or        aromatic monocyclic-heterocyclic ring system containing 1-4        heteroatoms selected from N, O and S, wherein 0-4 ring atoms of        the heterocyclic ring may be substituted with 0-4 R^(1d) groups;        and,    -   (d) an 8-10 membered fused heterocyclic bicyclic ring system,        containing 1-4 heteroatoms selected from N, O and S, wherein 0-4        ring atoms of the fused bicyclic ring system may be substituted        with 0-4 R^(1d) groups;        R^(1d) is a member selected from the group consisting of:    -   H, halo; C₁₋₆-alkyl, carbocylic aryl, —CN; —NO₂;        —(CH₂)₀₋₆—NR^(2d)R^(3d); —SO₂NR^(2d)R^(3d); —SO₂R^(2d); —CF₃;        —(CH₂)₀₋₆—OR^(2d); —OH, —OC₁₋₆alkyl, —O—(CH₂)₁₋₆OR^(2d);        —O—(CH₂)₁₋₆—C(═O)—O—R^(2d); —O—(CH₂)₁₋₆—C(═O)—N(R^(2d),R^(3d));        —N(R^(5a))—(CH₂)₁₋₆—OR^(2d);        —N(R^(5a))—(CH₂)₁₋₆—N(R^(2d),R^(3d)); —C(═O)—N(R^(2d),R^(3d));        —N(R^(5a))—(CH₂)₁₋₆—C(═O)—N(R^(2d),R^(3d));        —N(—(CH₂)₁₋₆—OR^(2d))₂; —N(R^(5a))—(CH₂)₁₋₆—OR^(2d);        —N(R^(5a))—C(═O)—R^(2d); —N(R^(5a))—SO₂—R^(2d);        —(CH₂)₀₋₆—C(═O)—O—R^(2d); —(CH₂)₀₋₆—C(═O)—N(R^(2d),R^(3d));        —(CH₂)₀₋₆—C(═NR^(2d))—N(R^(3d),R^(4d));        —(CH₂)₀₋₆—N(R^(5a))C(═NR^(2d))—N(R^(3d),R^(4d)); and a        —(CH₂)₀₋₆—N(R^(3d)) group which is attached via the nitrogen        atom to a carbon atom of a 5 to 6 membered saturated, partially        unsaturated or aromatic heterocyclic ring containing 1-4        heteroatoms selected from N, O and S, and a —(CH₂)₀₋₆— group        attached to a 5-6 membered saturated, partially unsaturated or        aromatic heterocyclic ring containing 1-4 heteroatoms selected        from N, O and S;        R^(5a),R^(2d),R^(3d) and R^(4d) are each independently a member        selected from the group consisting of:    -   H, C₁₋₆-alkyl and C₁₋₆-alkylaryl, —CN; —NO₂; carbocylic aryl,        —CN; —NO₂; or    -   R^(2d) and R^(3d) taken together with the N atoms they are        independently attached form a 5-7 membered saturated, partially        unsaturated or aromatic heterocyclic ring; or    -   R^(3d) and R^(4d) taken together with the N atom to which they        are attached form a 5-8 membered saturated, partially        unsaturated or aromatic heterocyclic ring containing 1-4        heteroatoms selected from N, O and S;        J is a member selected from the group consisting of:    -   a direct link, —O—, —NH—, —NMe-, —C(═O)—NH—, —NH—C(═O)—;        X is a member selected from the group consisting of:    -   (a) phenyl substituted with 0-3 R^(1e) groups;    -   (b) naphthyl substituted with 0-3 R^(1e) groups and    -   (c) a 6-membered aromatic heterocyclic ring system containing        1-3 N atoms and having 0-3 ring atoms substituted with 0-3        R^(1e) groups; and    -   (d) an 8-10 membered fused aromatic heterocyclic bicyclic ring        system containing 1-4 heteroatoms selected from N, O and S and        0-3 ring atoms of the fused heterocyclic bicyclic ring system        are substituted with 0-3 R^(1e) groups;        R^(1e) is a member independently selected from the group        consisting of:    -   Halo; CF₃; —C₁₋₄-alkyl; carbocyclic aryl; —C₀₋₂-alkyl-CN;        —O—R^(2e); —C₀₋₂-alkyl-C(═O)—O—R^(2e);        alkyl-C(═O)—N(R^(2e),R^(3e)); —C₀₋₂-alkyl-NO₂;        —C₀₋₂-alkyl-N(R^(2e),R^(3e)); —C₀₋₂-alkyl-SO₂—N(R^(2e),R^(3e));        —C₀₋₂-alkyl-SO₂—R^(2e); trihaloalkyl; —O—C₀₋₂-alkyl-O—R^(2e);        —C₀₋₂-alkyl-O—R^(2e); —O—C₁₋₄-alkyl-C(═O)—N(R^(2e),R^(3e));        —O—C₁₋₄-alkyl-C(═O)—O—R^(2e);        —C₀₋₂-alkyl-N(R^(2e))—C(═O)—R^(3e);        —C₀₋₂-alkyl-N(—R^(2e))—SO₂—R^(3e); —CH₂—N(R^(2e))—C(═O)—R^(3e);        —CH₂—N(R^(2e))—SO₂—R^(3e); —(CH₂)₀₋₆—NR^(2e)R^(3e);        —C(═O)—N(R^(2e),R^(3e)); —N(—(CH₂)₁₋₆—OR^(2e))₂;        —N(R¹⁰)—(CH₂)₁₋₆—OR^(2e); —N(R¹⁰)—C(═O)—R^(2e);        —N(R¹⁰)—SO₂—R^(2e); —C(N(R¹⁰))—N(R^(2e),R^(3e)); and a        —(CH₂)₀₋₆-5-6 membered saturated, partially unsaturated or        aromatic heterocyclic ring containing 1-4 heteroatoms selected        from N, O and S;        R¹⁰,R^(2e) and R^(3e) are each independently a member selected        from the group consisting of:    -   H; —C₀₋₂-alkyl-O—R^(1g); —R^(2g)); —C₁₋₄-alkyl-carbocyclic aryl;        —C₁₋₄-alkyl-heterocyclic; and R¹⁰ and R^(2e), or R^(2e) and        R^(3e) together with the N atom to which they are attached can        form 5-8 membered heterocyclic ring containing 1-4 heteroatoms        selected from N, O and S which can be substituted with 0-2        R^(1g) groups;        R^(1g) and R^(2g) are independently a member selected from the        group of:    -   H; halo; —C₁₋₄-alkyl, a carbocyclic aryl group; a saturated,        partially unsaturated or aromatic heterocyclic group; —CN;        —C(═O)—N(R^(3g),R^(4g)); —C(═O)—OR^(3g); —NO₂;        —(CH₂)_(p)—NR^(3g)R^(4g); —SO₂NR^(3g)R^(4g); —SO₂R^(3g); —CF₃;        and —(CH₂)_(p)OR^(3g);        p is an integer of 0-2; and        R^(3g) and R^(4g) are each independently selected from the group        consisting of:    -   H; C₁₋₄-alkyl and —C₀₋₄-alkyl-carbocyclic aryl;

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

Another preferred embodiment of formula I are compounds of formula (Ib):

A-Q-D-E-G-J-X  (Ib)

where:A is selected from:

-   -   (a) C₁-C₆-alkyl;    -   (b) C₃-C₈-cycloalkyl;    -   (c) —N(R¹,R²), N(R¹,R²)—C(═NR³)—, N(R¹,R²)—C(═NR³)—N(R⁴)—,        R¹—C(═NR³)—, R¹—C(═NR³)—N(R⁴)—;    -   (d) phenyl, which is independently substituted with 0-2 R        substitutuents;    -   (e) naphthyl, which is independently substituted with 0-2 R        substitutuents;    -   (f) a monocyclic or fused bicyclic ring system having from 5 to        10 ring atoms, wherein 1-4 ring atoms of the ring system are        selected from N, O and S, and wherein the ring system may be        substituted with 0-2 R substitutuents;        R is selected from:    -   H, halo, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,        —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —CF₃, —CN,        —(CH₂)_(m)—CO₂R¹, —(CH₂)_(m)C(═O)—N(R¹, R²),        —(CH₂)_(m)—C(═S)—N(R¹,R²), —NO₂, —(CH₂)_(m)—SO₂N(R¹,R²),        —(CH₂)_(m)—SO₂R¹, —(CH₂)_(m)NR¹R², —(CH₂)_(m)OR¹,        —(CH₂)_(m)—C(═NR³)—R¹, —(CH₂)_(m)—C(═NR³)—N(R¹,R²),        —(CH₂)_(m)—N(R⁴)—C(═NR³)—N(R¹,R²), and a 3-8 membered cyclic        system containing from 1-4 heteroatoms selected from N, O and S,        wherein from 1-4 hydrogen atoms on the heterocyclic ring system        may be independently replaced with a member selected from the        group consisting of halo, C₁-C₄-alkyl, —CN—C₁₋₄alkyl,        —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;        m is an integer of 0-2;        R¹,R²,R³ and R⁴ are independently selected from the group        consisting of:    -   H, —(CH₂)₀₋₄OR⁵, —(CH₂)₀₋₄—CO₂R⁵, —(CH₂)₀₋₄N(—R⁵, —R⁶),        —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl, —C₀₋₄alkylaryl and        —C₀₋₄alkylheteroaryl, and a 3-8 membered cyclic system        containing from 1-4 heteroatoms selected from N, O and S,        wherein from 1-4 hydrogen atoms on the heterocyclic ring system        may be independently replaced with a member selected from the        group consisting of halo, C₁-C₄-alkyl, —CN—C₁₋₄alkyl,        —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂; or    -   R¹ and R², or R² and R³ taken together can form a 3-8 membered        cycloalkyl or a heterocyclic ring system, wherein the        heterocyclic ring system may have from 3 to 10 ring atoms, with        1 to 2 rings being in the ring system and contain from 1-4        heteroatoms selected from N, O and S, where the hydrogen atoms        on the heterocyclic ring system may be independently replaced        with a member selected from the group consisting of halo,        C₁-C₄-alkyl, —CN, —CO₂R⁵, —OH, C₁₋₄alkyl, —C₂₋₆alkenyl,        —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl and        —NO₂;        R⁵ and R⁶ are independently selected from the group consisting        of:    -   H, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl, —C₀₋₄alkylaryl and        —C₀₋₄alkylheteroaryl, wherein from 1-4 hydrogen atoms on the        ring atoms of the phenyl and naphthyl moieties may be        independently replaced with a member selected from the group        consisting of halo, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,        —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —CN, and —NO₂; or    -   R⁵ and R⁶ taken together can form a 3-8 membered cycloalkyl or a        heterocyclic ring system, wherein the heterocyclic ring system        may have from 3 to 10 ring atoms, with 1 to 2 rings being in the        ring system and contain from 1-4 heteroatoms selected from N, O        and S, wherein from 1-4 hydrogen atoms on the heterocyclic ring        system may be independently replaced with a member selected from        the group consisting of halo, —C₁-C₄-alkyl, —CN—C₁₋₄alkyl,        —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;        Q is a member selected from the group consisting of:    -   a direct link, —CH₂—, —C(═O)—, —O—, —N(R⁷)—, —N(R⁷)CH₂—,        —CH₂N(R⁷)—, —C(═NR⁷)—, —C(═O)—N(R⁷)—, —N(R⁷)—C(═O)—, —S—, —SO—,        —SO₂—, —SO₂—N(R⁷)— and —N(R⁷)—SO₂—; preferably, Q is a member        selected from the group consisting of: a direct link, —CH₂—,        —C(═O)—, —O—, —NH—, —NMe-, —NHCH₂—, —NMeCH₂—, —CH₂NH—, —C(═NH)—,        —C(═O)—NH—, —NH—C(═O)—, —CH₂NMe-, —C(═NMe)-;        R⁷ is selected from:    -   H; —C₁₋₄-alkyl; —C₀₋₄-alkylaryl; —C₀₋₄-alkyl-heteroaryl; C₁₋₄        alkyl O—C₁₋₄ alkyl, C₁₋₄-alkyl N(C₁₋₄ alkyl, C₁₋₄-alkyl);        —C₁₋₄-alkyl-C(═O)—O—C₁₋₄-alkyl, and        —C₁₋₄-alkyl-C(═O)—N(—C₁₋₄-alkyl);        D is a direct link or is a member selected from the group        consisting of:    -   (a) phenyl, which is independently substituted with 0-2 R^(1a)        substitutuents;    -   (b) naphthyl, which is independently substituted with 0-2 R^(1a)        substitutuents; and    -   (c) a monocyclic or fused bicyclic heterocyclic ring system        having from 5 to 10 ring atoms, wherein 1-4 ring atoms of the        ring system are selected from N, O and S, and wherein the ring        system may be substituted from 0-2 R^(1a) substitutuents;        R^(1a) is selected from:    -   halo, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl, —CN, —NO₂, —(CH₂)_(n)OR^(2a),        —(CH₂)_(n)NR^(2a)R^(3a), —(CH₂)_(n)CO₂R^(2a),        —(CH₂)_(n)CONR^(2a)R^(3a), —SO₂NR^(2a)R^(3a), —SO₂R^(2a), —CF₃,        and a 5-6 membered aromatic heterocyclic system containing from        1-4 heteroatoms selected from N, O and S, wherein from 1-4        hydrogen atoms on the aromatic heterocyclic system may be        independently replaced with a member selected from the group        consisting of halo, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,        —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —CN and —NO₂;        R^(2a) and R^(3a) are independently selected from the group        consisting of:    -   H, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl, —C₀₋₄alkylaryl and        —C₀₋₄alkylheteroaryl, wherein from 1-4 hydrogen atoms on the        ring atoms of the phenyl and naphthyl moieties may be        independently replaced with a member selected from the group        consisting of halo, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,        —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —CN and —NO₂;        n is an integer of 0-2;        E is a direct link or a member selected from the group        consisting of:    -   —C₁₋₂-alkyl-, —S—, —SO—, —SO₂—, —O—C₀₋₁-alkyl-, —C₀₋₁-alkyl-O—,        —C₀₋₁-alkyl-N(—R⁸)—, —N(—R⁸)—C₀₋₁-alkyl-,        —C₀₋₁-alkyl-C(═O)—N(—R⁸)—C₀₋₁-alkyl,        —C₀₋₁-alkyl-N(—R⁸)—C(═O)—C₀₋₁-alkyl-, and        —C₀₋₁-alkyl-N(—R⁸)—C(═O)—N(—R⁸)—C₀₋₁-alkyl-; preferably, E is a        member selected from the group consisting of: a direct link,        —O—, —NH—, —CH₂NH—, —NHCH₂—, —CH₂O—, —OCH₂—, —NMe-,        —NH—C(═O)—NH—, —CH₂—NH—C(═O)—NH—, —C(═O)—NH—, —NH—C(═O)—;        —C(═O)—NMe-, —NMe-C(═O)—;        R⁸ is a member selected from the group consisting of:    -   H; —C₁₋₄-alkyl; —C₀₋₄-alkylaryl; —C₀₋₄-alkyl-heteroaryl;        —C₁₋₄-alkyl-OR^(2b), —C₁₋₄-alkyl-N(—R^(2b), —R^(3b));        —C₁₋₄-alkyl-C(═O)—OR^(2b); —C₁₋₄-alkyl-C(═O)—N(—R^(2b),        —R^(3b)); —C₀₋₄-alkyl-C(═O)—R^(2b); and —C₀₋₄-alkyl-SO₂—R^(2b);        R^(2b) and R^(3b) are each a member independently selected from        the group consisting of:    -   H, —C₁₋₄-alkyl, —C₁₋₄-alkyl-CO₂—C₀₋₄-alkyl, —C₀₋₄-alkyl-aryl;        —C₀₋₄-alkyl-heterocyclic group, and R^(2b) and R^(3b) together        with the N atom to which they are attached can form a 5-8        membered heterocyclic ring containing 1-4 heteroatoms selected        from N, O and S, wherein the heterocyclic ring may be        substituted with 0-2 R^(1c) groups;        R^(1c) is a member selected from the group consisting of:    -   Halo; —C₁₋₄-alkyl; —CN, —NO₂; —C(═O)—N(—R^(2c), —R^(3c));        —C(═O)—OR^(2c); —(CH₂)_(q)—N(—R^(2c), —R^(3c)); —SO₂—N(—R^(2c),        —R^(3c)); —SO₂R^(2c); —CF₃ and —(CH₂)_(q)—OR^(2c);        R^(2c) and R^(3c) are each independently a member selected from        the group consisting of:    -   H; —C₁₋₄-alkyl and —C₁₋₄-alkyl-aryl;        q is an integer of 0-2;        G is a member selected from the group consisting of:    -   (a) C₂-alkenyl or C₃₋₈-cycloalkenyl, wherein the alkenyl and        cycloalkenyl attachment points are the alkenyl carbon atoms and        wherein the —C₂-alkenyl or —C₃₋₈-cycloalkenyl are substituted        with 0-4 R^(1d) groups;    -   (b) a phenylene group wherein the ring carbon atoms of the        phenylene group are substituted with 0-4 R^(1d) groups;    -   (c) a 3-8 membered a saturated, partially unsaturated or        aromatic monocyclic ring system containing 1-4 heteroatoms        selected from N, O and S, wherein 0-2 ring atoms of the        heterocyclic ring may be substituted with 0-4 R^(1d) groups;        and,    -   (d) an 8-10 membered fused cyclic system, containing 0-4        heteroatoms selected from N, O and S, wherein 0-2 ring atoms of        the fused bicyclic ring system may be substituted with 0-4        R^(1d) groups;        R^(1d) is a member selected from the group consisting of:    -   H, halo; —CF₃; —OCF₃, —OCF₂H, —OCFH₂, —OCH₂CF₃, —OCF₂CF₃,        C₁₋₆-alkyl, carbocylic aryl, —CN; —NO₂; —(CH₂)₀₋₆—NR^(2d)R^(3d);        —(CH₂)₀₋₆—OR^(2d); —OH, —OC₁₋₆alkyl, —O—(CH₂)₁₋₆OR^(2d);        —O—(CH₂)₁₋₆—NR^(2d)R^(3d); —N(R^(5a))—(CH₂)₁₋₆—OR^(2d);        —N(R^(5a))—(CH₂)₁₋₆—N(R^(2d),R^(3d)); —(CH₂)₀₋₆—C(═O)—O—R^(2d);        —(CH₂)₀₋₆—C(═O)—N(R^(2d),R^(3d)); —O—(CH₂)₁₋₆—C(═O)—O—R^(2d);        —O—(CH₂)₁₋₆—C(═O)—N(R^(2d),R^(3d));        —N(R^(5a))—(CH₂)₁₋₆—C(═O)—O—R^(2d);        —N(R^(5a))—(CH₂)₁₋₆—C(═O)—N(R^(2d),R^(3d));        —N(—(CH₂)₁₋₆—OR^(2d))₂; —N(—(CH₂)₁₋₆—N(R^(2d),R^(3d)))₂;        —(CH₂)₀₋₆—SO₂NR^(2d)R^(3d); —(CH₂)₀₋₆—SO₂R^(2d);        —(CH₂)₀₋₆—N(R^(5a))—C(═O)—R^(2d);        —(CH₂)₀₋₆—N(R^(5a))—SO₂—R^(2d),        —(CH₂)₀₋₆—C(═NR^(2d))—N(R^(3d),R^(4d));        —(CH₂)₀₋₆—N(R^(5a))C(═NR^(2d))—N(R^(3d),R^(4d));        —(CH₂)₀₋₆—N(R^(5a))C(═NR^(2d))—R^(4d);        —O—(CH₂)₁₋₆—SO₂NR^(2d)R^(3d); —O—(CH₂)₁₋₆—SO₂R^(2d);        —O—(CH₂)₁₋₆—N(R^(5a))—C(═O)—R^(2d);        —O—(CH₂)₁₋₆—N(R^(5a))—SO₂—R^(2d),        —O—(CH₂)₁₋₆—C(═NR^(2d))—N(R^(3d),R^(4d));        —O—(CH₂)₁₋₆—N(R^(5a))C(═NR^(2d))—N(R^(3d),R^(4d));        —O—(CH₂)₁₋₆—N(R^(5a))C(═NR^(2d))—R^(4d);        —N(R^(5d))—(CH₂)₁₋₆—SO₂NR^(2d)R^(3d);        —N(R^(5d))—(CH₂)₁₋₆—SO₂R^(2d);        —N(R^(5d))—(CH₂)₁₋₆—N(R^(5a))—C(═O)—R^(2d);        —N(R^(5d))—(CH₂)₁₋₆—N(R^(5a))—SO₂—R^(2d),        —N(R^(5d))—(CH₂)₁₋₆—C(═NR^(2d))—N(R^(3d),R^(4d));        —N(R^(5d))—(CH₂)₁₋₆—N(R^(5a))C(═NR^(2d))—N(R^(3d),R^(4d));        —N(R^(5d))—(CH₂)₁₋₆—N(R^(5a))C(═NR^(2d))—R^(4d); and a 3-8        membered cyclic system containing from 1-4 heteroatoms selected        from N, O and S, wherein from 1-4 hydrogen atoms on the        heterocyclic ring system may be independently replaced with a        member selected from the group consisting of halo, C₁-C₄-alkyl,        —CN—C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,        —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;        R^(5a),R^(2d),R^(3d),R^(4d) and R^(5d) are each independently a        member selected from the group consisting of:    -   H, C₁₋₆-alkyl and C₁₋₆-alkylaryl, —CN; —NO₂; or    -   R^(2d) and R^(3d), or R^(3d) and R^(4d) taken together with the        N atoms they are independently attached form a 3-8 membered        saturated, partially unsaturated or aromatic heterocyclic ring;        J is a direct link or is a member selected from the group        consisting of:    -   —N(—R⁹)—C(═O)—; —C(═O)—N(—R⁹)—; —O—; —S—; —SO—; —SO₂—;        —SO2N(R⁹)—, —CH₂—; —N(—R⁹)—; and —N(—R⁹)—SO₂—; preferably, J is        a member selected from the group consisting of: a direct link,        —O—, —SO2-, —SO2NH—, —NH—, —NMe-, —C(═O)—NH—, —NH—C(═O)—;        R⁹ is a member selected from the group consisting of:    -   H; —C₁₋₄-alkyl; —C₀₋₄-alkylaryl; —C₀₋₄-alkyl-heteroaryl;        —C₁₋₄-alkyl-OR^(6a), —C₁₋₄-alkyl-N(—R^(6a), —R^(6b));        —C₁₋₄-alkyl-C(═O)—OR^(6a), and —C₁₋₄-alkyl-C(═O)—N(—R^(6a),        —R^(6b));        R^(6a) and R^(6b) are each a member independently selected from        the group consisting of:    -   H and —C₁₋₆-alkyl;        X is a member selected from the group consisting of:    -   (a) phenyl substituted with 0-3 R^(1e) groups;    -   (b) naphthyl substituted with 0-3 R^(1e) groups and    -   (c) a 6-membered aromatic heterocyclic ring system containing        1-3 N atoms and having 0-3 ring atoms substituted with 0-3        R^(1e) groups; and    -   (d) an 8-10 membered fused bicyclic ring system containing 1-4        heteroatoms selected from N, O and S and 0-3 ring atoms of the        fused heterocyclic bicyclic ring system are substituted with 0-3        R^(1e) groups;        R^(1e) is a member independently selected from the group        consisting of:    -   Halo; CF₃; —C₁₋₄-alkyl; carbocyclic aryl; —C₀₋₂-alkyl-CN;        —O—R^(2e); —C₀₋₂-alkyl-C(═O)—O—R^(2e);        —C₀₋₂-alkyl-C(═O)—N(R^(2e),R^(3e)); —C₀₋₂-alkyl-NO₂;        —C₀₋₂-alkyl-N(R^(2e),R^(3e)); —C₀₋₂-alkyl-SO₂—N(R^(2e),R^(3e));        —C₀₋₂-alkyl-SO₂—R^(2e); trihaloalkyl; —O—C₀₋₂-alkyl-O—R^(2e);        —C₀₋₂-alkyl-O—R^(2e); —O—C₁₋₄-alkyl-C(═O)—N(R^(2e); R^(3e));        —O—C₁₋₄-alkyl-C(═O)—O—R^(2e);        —C₀₋₂-alkyl-N(R^(2e))—C(═O)—R^(3e);        —C₀₋₂-alkyl-N(—R^(2e))—SO₂—R^(3e); —CH₂—N(R^(2e))—C(═O)—R^(3e);        —CH₂—N(R^(2e))—SO₂—R^(3e); —(CH₂)₀₋₆—NR^(2e)R^(3e);        —C(═O)—N(R^(2e),R^(3e)); —N(—(CH₂)₁₋₆—OR^(2e))₂,        —N(R¹⁰)—(CH₂)₁₋₆—OR^(2e); —N(R¹⁰)—C(═O)—R^(2e);        —N(R¹⁰)—SO₂—R^(2e); —C(N(R¹⁰))—N(R^(2e),R^(3e)); and a        —(CH₂)₀₋₆-5-6 membered saturated, partially unsaturated or        aromatic heterocyclic ring containing 1-4 heteroatoms selected        from N, O and S;        R¹⁰,R^(2e) and R^(3e) are each independently a member selected        from the group consisting of:    -   H; C₁₋₄-alkyl; —C₀₋₂-alkyl-O—(R^(1g); —R^(2g));        —C₁₋₄-alkyl-carbocyclic aryl; —C₁₋₄-alkyl-heterocyclic; and R¹⁰        and R^(2e), or R^(2e) and R^(3e) together with the N atom to        which they are attached can form 5-8 membered heterocyclic ring        containing 1-4 heteroatoms selected from N, O and S which can be        substituted with 0-2 R^(1g) groups;        R^(1g) and R^(2g) are independently a member selected from the        group of:    -   H; halo; —C₁₋₄-alkyl, a carbocyclic aryl group; a saturated,        partially unsaturated or aromatic heterocyclic group; —CN;        —C(═O)—N(R^(3g))R^(4g); —C(═O)—OR^(3g); —NO₂;        —(CH₂)_(p)—NR^(3g)R^(4g); —SO₂NR^(3g)R^(4g); —SO₂R^(3g); —CF₃;        and —(CH₂)_(p)OR^(3g);        p is an integer of 0-2;        R^(3g) and R^(4g) are each independently selected from the group        consisting of:    -   H; C₁₋₄-alkyl and —C₀₋₄-alkyl-carbocyclic aryl;

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

Another preferred embodiment of formula I are compounds of formula (Ic):

A-Q-D-E-G-J-X  (Ic)

where:A is a member selected from the group consisting of:

Q is a member selected from the group consisting of:

-   -   a direct link, —C(═O)—, —NH—, —NMe-, —NHCH₂—, —NMeCH₂—,        —C(═NH)—, —C(═NMe)-;        D is a direct link or is a member selected from the group        consisting of:

E is a member selected from the group consisting of:

-   -   a direct link, —CH₂NH—, —C(═O)—NH—, —NH—C(═O)—;        G is a member selected from the group consisting of:

G is substituted by 0-4 R^(1d) groups and each R^(1d) group isindependently selected from the group consisting of:

J is a member selected from the group consisting of:

-   -   a direct link, —O—, —NH—, —C(═O)—NH— and —NH—C(═O)—;        X is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

Still another preferred embodiment of the invention are compounds of thefollowing formula (II):

where:R^(1a) is a member selected from the group consisting of:

-   -   H, —F, —Cl and —Br;        R^(1e) is a member selected from the group consisting of:    -   H, —F, —Cl, —Br, —OMe, —OH, -Me, —CF₃ and —CH₂NH₂; and        A-Q is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

Still another preferred embodiment the invention are compounds offormula (III):

where:R^(1a) is a member selected from the group consisting of:

-   -   H, —F, —Cl and —Br;        R^(1e) is a member selected from the group consisting of:    -   H, —F, —Cl, —Br, —OMe, —OH, -Me, —CF₃ and —CH₂NH₂; and        A-Q is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

Another further preferred embodiment of the invention are compoundsaccording to the formula (IV):

where:R^(1a) is a member selected from the group consisting of:

-   -   H, —F, —Cl and —Br;        R^(1e) is a member selected from the group consisting of:    -   H, —F, —Cl, —Br, —OMe, —OH, -Me, —CF₃ and —CH₂NH₂;        A-Q is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

Still another preferred embodiment of the invention are compounds offormula (V):

where:R^(1e) is a member selected from the group consisting of:

-   -   H, —F, —Cl, —Br, —OMe, —OH, -Me, —CF₃ and —CH₂NH₂;        A-Q is a member selected from the group consisting of:

andD is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

In another preferred embodiment, the present invention provides acompound according to the formula:

where:J is a member selected from the group consisting of:

-   -   —NHC(═O)—, —C(═O)NH—;        X is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

In another embodiment the present invention provides a compoundaccording to the formula:

wherein:R is a member selected from the group of:

-   -   —SO₂—NH₂ and —SO₂Me;        R^(1a) is a member selected from the group of:    -   H, —F, —Cl and Br;        E is a member selected from the group consisting of:    -   —NHC(═O)— and —C(═O)NH—;        R^(1d1),R^(1d2), and R^(1d4) are independently a member selected        from the group of:    -   H, —F, —Cl, —Br, -Me, —NO₂, —OH, —OMe, —NH₂, —NHAc, —NHSO₂Me,        —CH₂OH and —CH₂NH₂;        R^(1d3) is a member selected from the group of:

R^(1e) is a member selected from the group of:

-   -   F, —Cl, —Br, —OH, -Me and —OMe,

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

In another further preferred embodiment, the present invention providesa compound according to the formula:

wherein:R is a member selected from the group consisting of:

-   -   —SO₂NH₂, —SO₂Me;        R^(1a) is a member selected from the group consisting of:    -   H, —F, —Cl and Br;        R^(1e) is a member selected from the group consisting of:    -   H, —F, —Cl, —Br, —OMe, —OH, -Me, —CF₃ and —CH₂NH₂; and        G is a member selected from the group consisting of:

wherein each G group may be substituted by 0-4 R^(1d) groups and eachsuch R^(1d) group is independently selected from the group consistingof:

-   -   H, —CH₃, —CF₃, —F, —Br, —NH₂, —N(-Me)₂, —OH, —OMe, —NHSO₂Me,        —NO₂, —CN, —C(═O)—OMe, —CO₂H, —C(═O)—NH₂, —SO₂NH₂, —SO₂CH₃,        —NH—C(═O)-Me, —C(═O)—N(-Me)₂, —CH₂NH₂, —CH₂—N(-Me)₂, —CH₂OH,        —OCH₂CO₂H, —OCH₂CO₂Me, —OCH₂C(═O)—NH₂, —OCH₂C(═O)—N(-Me)₂,

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

In another further preferred embodiment the present invention provides acompound according to the formula:

wherein:J-X are collectively a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

In another further preferred embodiment the present invention provides acompound according to the formula:

wherein:R is a member selected from the group of:

-   -   —SO₂NH₂, and —SO₂Me;        R^(1a) is a member selected from the group of:    -   H, —F, —Cl and Br;        E is a member selected from the group consisting of:    -   —NHC(═O)— and —C(═O)NH—;        J is a member selected from the group consisting of:    -   —NHC(═O)— and —C(═O)NH—, O;        R^(1d1),R^(1d2), and R^(1d4) are independently a member selected        from the group of:    -   H, —F, —Cl, —Br, -Me, —NO₂, —OH, —OMe, —NH₂, —NHAc, —NHSO₂Me,        —CH₂OH, —CH₂NH₂;        R^(1d3) is a member selected from the group of:

R^(1e) is a member selected from the group of:

-   -   F, —Cl, —Br, —OH, -Me and —OMe;

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

In another preferred embodiment, the present invention provides acompound of the following formulae, which illustrate the compoundshaving preferred substituents for G, particularly when G is a pyrazolering structure.

wherein:R is a member selected from the group of:

-   -   —SO₂—NH₂, and —SO₂Me;        R^(1a) is a member selected from the group of:    -   H, —F, —Cl and Br;        R^(1d) is a member selected from the group consisting of:    -   —H, —CH₃, —CF₃, —CN, —SO₂NH₂ and —SO₂CH₃; and        R^(1e) is a member selected from the group of:    -   —Cl and —Br;

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

In another preferred embodiment, the present invention provides acompound of the following formulae, which illustrate the compoundshaving preferred substituents for A-Q taken collectively when theremainder of the compound structure has the one of the following twoformulae:

wherein:A-Q taken together are a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

In another preferred embodiment the present invention provides acompound according to the formula:

wherein:A-Q is a member selected from the group of:

where A-Q may optionally be further substituted with at least one Z′group, where each Z′ group is independently a C₁-C₆ alkyl, preferably aC₁-C₃ alkyl group, most preferably a methyl group and where each Z′group may optionally be substituted with a hydroxyl, carboxylic acid orcarboxylic acid C₁-C₆ ester group, preferably a hydroxyl, carboxylicacid or carboxylic acid C₁-C₃ ester group, and most preferably, ahydroxyl, carboxylic acid or carboxylic acid methyl ester;R^(1a) is a member selected from the group of:

-   -   H, —F, —Cl and Br;        R^(1d1),R^(1d2), and R^(1d4) are independently a member selected        from the group of:    -   H, —F, —Cl, —Br, -Me, —NO₂, —OH, —OMe, —NH₂, —NHAc, —NHSO₂Me,        —CH₂OH, —CH₂NH₂        R^(1d3) is a member selected from the group of:

R^(1e) is a member selected from the group of:

-   -   F, —Cl, —Br, —OH, -Me and —OMe;

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

In another embodiment, the invention provides a compound of formula VI:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

In formula VI:

Z′ and Z″ are each independently a C₁-C₆ alkyl, preferably a C₁-C₃ alkylgroup, most preferably a methyl group; where Z′ and Z″ may be optionallysubstituted with a hydroxyl, carboxylic acid or carboxylic acid C₁-C₆ester group, preferably a hydroxyl, carboxylic acid or carboxylic acidC₁-C₃ ester group, and most preferably, a hydroxyl, carboxylic acid orcarboxylic acid methyl ester;

R^(1a) is a member selected from the group of H, —F, —Cl and Br;

R^(1d2) and R^(1d4) are each H;

R^(1d1) and R^(1d3) are each independently a member selected from thegroup of H, —Cl, —F, —Br, —OH and —OMe; and

R^(1e) is a member selected from the group of —F, —Cl, —Br, —OH, -Me and—OMe.

Examples of suitable compounds of formula VI, as described above,include, but are not limited to:

In another embodiment, the invention further provides a compound offormula VII:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.In formula VII:

A-Q is a member selected from the group of:

where Z′ is as described above;R^(1a) is a member selected from the group of H, —F, —Cl and Br;R^(1d2) and R^(1d4) are each H;R^(1d1) is R^(1d3) are each independently a member selected from thegroup of H, —F, —Br, —OH and —OMe;R^(1e) is a member selected from the group of —F, —Cl, —Br, —OH, -Me and—OMe.Examples of suitable compounds of formula VII, as described above,include, but are not limited to:

In another further preferred embodiment the present invention providesthe following compounds:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

In another further preferred embodiment the present invention providesthe following compounds:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

The invention also provides compounds of formula Ib, as set forth above,wherein:

A is a member selected from the group consisting of:

Q is a member selected from the group consisting of:

-   -   a direct link, —CH₂—, —C(═O)—, —NH—, —N(Me)—, —NHCH₂—,        —N(Me)CH₂—, C(═NH)—, —C(═NMe)-;        D is a direct link or is a member selected from the group        consisting of:

E is a member selected from the group consisting of:

-   -   a direct link, —CH₂NH—, —NHCH₂—, —CH₂O—, —OCH₂—, —CH₂NH—,        —CONH—, —NHCO—, —CONMe-, —NMeCO—;        G is a member selected from the group consisting of:

G is substituted by 0-4 R^(1d) groups and each R^(1d) group isindependently selected from the group consisting of:

J is a member selected from the group consisting of:

-   -   a direct link, —SO₂—, —CO—, —O—, —NH—, —C(═O)—NH— and        —NH—C(═O)—;        X is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

where:R^(1a) is a member selected from the group consisting of:

-   -   H, —F, —Cl and —Br;        R^(1e) is a member selected from the group consisting of:    -   H, —F, —Cl, —Br, —OMe, —OH, -Me, —CF₃ and —CH₂NH₂; and        A-Q is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

The invention provides compound of formula Ib, having the followingstructure:

wherein:R is a member selected from the group consisting of:

-   -   —SO₂Me, —SO₂NH₂, —CH₂NH₂, —CH₂N(CH₃)₂;        R^(1a) is a member selected from the group consisting of:    -   H, —F;        R^(1d1) is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

wherein:A-Q is a member selected from the group consisting of:

R^(1a) is a member selected from the group consisting of:

-   -   H, —F;        R^(1d1) is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

wherein:A-Q is a member selected from the group consisting of:

R^(1a) is a member selected from the group consisting of:

-   -   H, —F;        R^(1e) is a member selected from the group consisting of:    -   H, —F, —SO₂Me, —SO₂NH₂, —CN, —CONH₂, —CH₂NH₂, —CH₂NMe₂;        R^(1d3) is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

wherein:A-Q is a member selected from the group consisting of:

R^(1a) is a member selected from the group consisting of:

-   -   H, —F;        R^(1e) is a member selected from the group consisting of:    -   —Cl, —Br;        R^(1d3) is a member selected from the group consisting of:    -   H, F, Cl, Br, —OCH₃, —OCF₃, —OCH₂F, —OCHF₂, —OCH₂CF₃, —OCF₂CF₃;        and all pharmaceutically acceptable isomers, salts, hydrates,        solvates and prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

wherein:A-Q is a member selected from the group consisting of:

R^(1a) is a member selected from the group consisting of:

-   -   H, —F;        R^(1d3) is a member selected from the group consisting of:    -   H, —F, —Cl, —Br, —OCH₃, —OCF₃, —OCH₂F, —OCHF₂, —OCH₂CF₃,        —OCF₂CF₃, —NHSO₂Me, —NHAc, —SO₂Me, —SO₂NH₂;        X is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

wherein:A-Q is a member selected from the group consisting of:

andR^(1a) is a member selected from the group consisting of:

-   -   H, —F;        and all pharmaceutically acceptable isomers, salts, hydrates,        solvates and prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

wherein:R^(1a) is a member selected from the group consisting of:

-   -   H, —F;        R^(1d1) is a member selected from the group consisting of:    -   H, —OMe;        R^(1d3) is a member selected from the group consisting of:    -   H, —F, —Cl, —Br, —OMe, —OCF₃;        R^(1e) is a member selected from the group consisting of:    -   H, —F, —Cl, —Br;        A-Q is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

wherein:D is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

wherein:

R^(1d1) is H or —OMe;

A-Q-D is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

wherein:

R^(1a) is H or F; R^(1d1) is H or —OMe;

A-Q is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

wherein:

R^(1a) is H or F; R^(1d1) is H or —OMe;

A-Q is a member selected from the group consisting of:

andR^(1a) is a member selected from the group consisting of: H, —F,and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

wherein:

R^(1a) is H or F; R^(1d1) is H or —OMe; and

A-Q is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

wherein:A-Q is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

wherein:

R^(1a) is H or F; R^(1d1) is H or —OMe;

A-Q is a member selected from the group consisting of:

and X is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

The invention provides compound of formula Ib, as describe above, havingthe following structure:

wherein:

R1a is H or F;

A-Q is a member selected from the group consisting of:

R^(1d1) is a member selected from the group consisting of:

R^(1d3) is a member selected from the group consisting of:

-   -   H, —F, —Cl, —Br, —OCH₃, —OCF₃, —OCH₂F, —OCHF₂, —OCH₂CF₃,        —OCF₂CF₃; and        X is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

wherein:A-Q is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

wherein:A-Q is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

wherein:

R^(1a) is H or F;

A-Q is a member selected from the group consisting of:

R^(1d1) is a member selected from the group consisting of: H, OMe, Cl,F, OCF₃,

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

wherein:

R^(1a) is H or F;

A-Q is a member selected from the group consisting of:

R^(1d1) is a member selected from the group consisting of:

-   -   H, —F, —Cl, —Br, —OMe, —OCF₃, —OH, —NMe₂, —OCH₂CO₂Et, —OCH₂CO₂H;        R^(1d3) is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

wherein:

R^(1a) is H or F;

A-Q is a member selected from the group consisting of:

R^(1d1) is a member selected from the group consisting of:

R^(1d3) is a member selected from the group consisting of:

-   -   H, —F, —Cl, —Br, —OMe, —OCF₃, —OH, —NMe₂, —OCH₂CO₂Et, —OCH₂CO₂H,        —OCF₂H, —OCFH₂, —OCF₂CF₃, —OCH₂CH₃,        and all pharmaceutically acceptable isomers, salts, hydrates,        solvates and prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

wherein:

R^(1a) is H or F;

R^(1d1) is selected from H, —OMe, —NMe₂,

R^(1d3) is Cl or Br;

A-Q is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

wherein:

R^(1a) is H or F;

R^(1d1) is selected from H, —OMe, —NMe₂,

R^(1d3) is Cl or Br;

A-Q is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

wherein:

R^(1a) is H or F;

R^(1d1) is selected from H, —OMe, —NMe₂,

A-Q is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

wherein:

R^(1a) is H or F;

R^(1d1) is selected from H, —OMe, —NMe₂,

R^(1d3) is or —Br;

A-Q is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

The invention provides a compound of formula Ib, as described above,having the following structure:

wherein:

R^(1a) is H or F;

R^(1d1) is selected from H, —OMe, —NMe₂,

and

R^(1d3) is or —Br;

A-Q is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

wherein:

R^(1a) is H or F;

R^(1d1) is selected from H, —OMe, —NMe₂,

and

R^(1d3) is or —Br;

A-Q is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

wherein:A-Q is a member selected from the group consisting of:

R^(1a) is a member selected from the group consisting of:

-   -   H, —F, —Cl and Br;        R^(1e) is a member selected from the group consisting of:    -   H, —F, —Cl, —Br, —OMe, —OH, -Me, —CF₃ and —CH₂NH₂; and        G is a member selected from the group consisting of:

wherein each G group is substituted by 0-4 R^(1d) groups and each suchR^(1d) group is independently selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

wherein:

-   -   A-Q is a member selected from the group of:

R^(1a) is a member selected from the group of:

-   -   H, —F, —Cl, —Br;        R^(1d) is a member selected from the group of:    -   H, —F, —Cl, —Br, —OMe;        R^(1e1) is a member selected from the group of:    -   H, —F, —Cl, —Br, —NH₂, —CH₂NH₂, —OMe, —OH, —CN, —SO₂Me, —SO₂NH₂;        and        R^(1e2) is a member selected from the group of:    -   H, —F, —Cl, —Br, —NH₂,        and all pharmaceutically acceptable isomers, salts, hydrates,        solvates and prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

wherein:A-Q is a member selected from the group of:

R^(1a) is a member selected from the group of:

-   -   H, —F, —Cl and Br; and        R^(1d) is a member selected from the group of:    -   H, —F, —Cl, —Br, —OMe,        and all pharmaceutically acceptable isomers, salts, hydrates,        solvates and prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

wherein:A-Q is a member selected from the group of:

R^(1a) is a member selected from the group of:

-   -   H, —F, —Cl and Br; and        R^(1e) is a member selected from the group of:    -   H, —F, —Cl, —Br, —NH₂, —CH₂NH₂, —OMe, —OH, —CN, —SO₂Me, —SO₂NH₂,        and all pharmaceutically acceptable isomers, salts, hydrates,        solvates and prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

wherein:R is a member selected from the group of:

-   -   —SO₂NH₂, —SO₂Me. —CH₂NMe₂;        R^(1a) is a member selected from the group of:    -   H, —F, —Cl, —Br;        R^(1d) is a member selected from the group of:    -   H, —F, —Cl, —Br, —CN, CF₃, —CH₃, —SO₂NH₂, —SO₂Me; and        R^(1e) is a member selected from the group of:    -   —Cl, —Br,        and all pharmaceutically acceptable isomers, salts, hydrates,        solvates and prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

wherein:A-Q taken together are a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

wherein:A-Q is a member selected from the group consisting of:

R^(1a) is a member selected from the group consisting of:

-   -   H, —F, —Cl and Br;        G is a member selected from the group consisting of:

wherein each G group is substituted by 0-4 R^(1d) groups and each suchR^(1d) group is independently selected from the group consisting of:

J is a member selected from the group consisting of:

-   -   —CONH—, —NHCO—, —O—, —NH—, —NMe-, —CONMe-, —NMeCO—; and        X is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

wherein:A-Q is a member selected from the group of:

R^(1a) is a member selected from the group of:

-   -   H, —F, —Cl, —Br;        R^(1d1),R^(1d2),R^(1d3) and R^(1d4) is independently a member        selected from the group of:    -   H, —F, —Cl, —Br, —NO₂, —NH₂, —NHMe, —NMe₂, —NHAc, —NHSO₂Me,        —SO₂Me, —CO₂H, —CO₂Me, —OH, —OMe, —N(Me)CO₂H, —N(Me)CO₂Et and

andR^(1e) is a member selected from the group of:

-   -   H, —OH,        and all pharmaceutically acceptable isomers, salts, hydrates,        solvates and prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

R is a member selected from the group of:

-   -   —SO₂Me, —SO₂NH₂, —CH₂NH₂, —CH₂N(CH₃)₂;        R^(1a) is a member selected from the group of:    -   H, —F;        R^(1d2) and R^(1d3) is independently a member selected from the        group of:    -   H, —F, —Cl, —Br, —NO₂, —NH₂, —NHMe, —NMe₂, —NHAc, —NHSO₂Me,        —SO₂Me, —CO₂H, —CO₂Me, —OH, —OMe; and        R^(1e) is a member selected from the group of:    -   H, —OH,        and all pharmaceutically acceptable isomers, salts, hydrates,        solvates and prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

wherein:R is a member selected from the group of:

-   -   —SO₂Me, —SO₂NH₂, —CH₂NH₂, —CH₂N(CH₃)₂;        R^(1a) is a member selected from the group of:    -   H, —F;        R^(1d2) and R^(1d3) is independently a member selected from the        group of:    -   H, —F, —Cl, —Br, —NO₂, —NH₂, —NHMe, —NMe₂, —NHAc, —NHSO₂Me,        —SO₂Me, —CO₂H, —CO₂Me, —OH, —OMe; and        R^(1e) is a member selected from the group of:    -   H, —OH,        and all pharmaceutically acceptable isomers, salts, hydrates,        solvates and prodrug derivatives thereof.

The invention provides compound of formula Ib, as described above,having the following structure:

R is a member selected from the group of:

-   -   —SO₂Me, —SO₂NH₂, —CH₂NH₂, —CH₂N(CH₃)₂;        R^(1a) is a member selected from the group of:    -   H, —F;        R^(1d1) and R^(1d2) is independently a member selected from the        group of:    -   H, —F, —Cl, —Br, —OMe; and        R^(1e) is a member selected from the group of:    -   H, —OH,        and all pharmaceutically acceptable isomers, salts, hydrates,        solvates and prodrug derivatives thereof.

The following preferred embodiments of the present invention illustratecompounds wherein the central aromatic ring structure is divalentphenylene, however divalent 6 membered heteroaromatic rings having from1 to 3 nitrogen atoms may be substituted for the bivalent phenylenestructure. Further the terminal aromatic ring substituted which issubstituted by a R^(1e) group as illustrated below in the preferredembodiments is either a phenyl or a 2-pyridyl group, however other 6membered heteroaromatic rings having from 1 to 3 nitrogen atoms can besubstituted for either the phenyl or 2-pyridyl. Moreover, 2 to 3additional R^(1e) groups other than hydrogen may each be independentlysubstituted for a hydrogen atom attached to a ring carbon on theterminal rings illustrated or substituted for the illustrated terminalring structure.

A preferred embodiment of the invention provides a compound of formulaVIII:

wherein:

R^(1a) is a member selected from the group of H, —F, —Cl and Br;

R^(1d2) and R^(1d4) are each H or F;

R^(1d1) and R^(1d3) are each independently a member selected from thegroup of H, Cl, —F, —Br, —OH, —OMe, —OCF₃, OCHF₂, OCH₂F, —NH₂, —NMe₂,—OCH₂COOEt, —OCH₂COOH, —N(Me)CH₂COOH, —N(Me)COOEt, and,

R^(1e) is a member selected from the group of —F, —Cl, —Br, —OH, -Me and—OMe;

A-Q is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

Another preferred embodiment provides a compound of formula VIII havingthe following structure:

wherein:

R^(1a) is a member selected from the group of H, or —F;

R^(1d1) is each independently a member selected from the group of H,—OMe, —NMe₂, —OCH₂COOEt, —OCH₂COOH, —N(Me)CH₂COOH, —N(Me)COOEt,

R^(1d3) are independently a member selected from the group of H, —Cl,—Br, —F, and —OMe;

R^(1e) is a member selected from the group of —Cl, and —Br;

A-Q is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

Another preferred embodiment according to the present invention providesan individual compound, which is a member selected from the followingstructures:

whereinR^(1d3) is a member selected from the group consisting of:

H, —F, —Cl, —Br, —OMe, —OCF₃, —OCF₂H, and —OCF₂H;

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

A still further embodiment of the present invention provides a compoundaccording to the formula IX, as follow:

wherein:

R^(1a) is a member selected from the group of H, —F, —Cl and Br;

R^(1d2) and R^(1d4) are each H or F;

R^(1d1) and R^(1d3) are each independently a member selected from thegroup of H, —Cl, —F, —Br, —OH, —OMe, —OCF₃, OCHF₂, OCH₂F, —NH₂, —NMe₂,—OCH₂COOEt, —OCH₂COOH, —N(Me)CH₂COOH, —N(Me)COOEt,

R^(1e) is a member selected from the group of —F, —Cl, —Br, —OH, -Me and—OMe;

A-Q is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

A particularly preferred embodiment of the present invention providessuch compounds having the following formula:

wherein:

R^(1a) is a member selected from the group of H, or —F

R^(1d1) is each independently a member selected from the group of H,—OMe, —NMe₂, —OCH₂COOEt, —OCH₂COOH, —N(Me)CH₂COOH, —N(Me)COOEt, and,

R^(1d3) are independently a member selected from the group of H, —Cl,—Br, —F, and —OMe,

R^(1e) is a member selected from the group of —Cl, and —Br,

A-Q is a member selected from the group consisting of:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

A still further embodiment of the present invention provides anindividual compound which is a member selected from the followingstructures:

whereinR^(1d3) is a member selected from the group consisting of:

H, —F, —Cl, —Br, —OMe, —OCF₃, —OCF₂H, and —OCF₂H,

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

Another preferred embodiment of the present invention provides compoundsaccording to the invention as illustrated herein, wherein the A-Q-substituent is an amidino substituent, the amine portion of which is acyclized amine heterocyclic ring, preferably a saturated cyclized amineheterocyclic ring, and the cyclized amine ring is substituted by 1-3members. Examples of such A-Q substituents include but are not limitedto:

wherein each of R^(a),R^(b),R^(d) and R^(e) is independently a memberselected from the group consisting of C₁-C₈ alkyl, C₂-C₈ alkenyl, C₁-C₈acyl and C₁-C₈ acyl C₁-C₈ alkyl ester, and the Ra and Rb groups togetherwith the nitrogen atom to which they are both attached may be cyclizedto form a C₃-C₈ heterocylic ring having from 1 to 4 additional heteroring atoms selected from O, N and S,and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

Another preferred embodiment is an embodiment wherein the amidino groupsillustrated above as substituents for the cyclized amine heterocyclicring are instead form an acyclic amidino A-Q group and allpharmaceutically acceptable isomers, salts, hydrates, solvates andprodrug derivatives thereof.

Such compounds are formed by reacting the appropriate acyclic amine orcycliczed amine with an amidino group or with a thioimino group whereinthe remainder of the structures D-E-G-J-X are defined as in formula I oras in a preferred D-E-G-J-X structure illustrated in a preferredembodiment herein. Other ways to produce such compound structures willbe apparent to an ordinary praticitioner in this field uponconsideration of the description herein and the illustrated preferredembodiments.

This invention also encompasses all pharmaceutically acceptable isomers,salts, hydrates, solvates, and prodrug derivatives of the preferredcompounds. In addition, the preferred compounds can exist in variousisomeric and tautomeric forms, and all such forms are meant to beincluded in the invention, along with pharmaceutically acceptable salts,hydrates, solvates, and prodrug derivatives of such isomers andtautomers.

The compounds of this invention may be isolated as the free acid or baseor converted to salts of various inorganic and organic acids and bases.Such salts are within the scope of this invention. Non-toxic andphysiologically compatible salts are particularly useful although otherless desirable salts may have use in the processes of isolation andpurification.

A number of methods are useful for the preparation of the saltsdescribed above and are known to those skilled in the art. For example,the free acid or free base form of a compound of one of the formulasabove can be reacted with one or more molar equivalents of the desiredacid or base in a solvent or solvent mixture in which the salt isinsoluble, or in a solvent like water after which the solvent is removedby evaporation, distillation or freeze drying. Alternatively, the freeacid or base form of the product may be passed over an ion exchangeresin to form the desired salt or one salt form of the product may beconverted to another using the same general process.

Prodrug Derivatives of Compounds

This invention also encompasses prodrug derivatives of the compoundscontained herein. The term “prodrug” refers to a pharmacologicallyinactive derivative of a parent drug molecule that requiresbiotransformation, either spontaneous or enzymatic, within the organismto release the active drug. Prodrugs are variations or derivatives ofthe compounds of this invention which have groups cleavable undermetabolic conditions. Prodrugs become the compounds of the inventionwhich are pharmaceutically active in vivo, when they undergo solvolysisunder physiological conditions or undergo enzymatic degradation. Prodrugcompounds of this invention may be called single, double, triple etc.,depending on the number of biotransformation steps required to releasethe active drug within the organism, and indicating the number offunctionalities present in a precursor-type form. Prodrug forms oftenoffer advantages of solubility, tissue compatibility, or delayed releasein the mammalian organism (see, Bundgard, Design of Prodrugs, pp. 7-9,21-24, Elsevier, Amsterdam 1985 and Silverman, The Organic Chemistry ofDrug Design and Drug Action, pp. 352-401, Academic Press, San Diego,Calif., 1992). Prodrugs commonly known in the art include acidderivatives well known to practitioners of the art, such as, forexample, esters prepared by reaction of the parent acids with a suitablealcohol, or amides prepared by reaction of the parent acid compound withan amine, or basic groups reacted to form an acylated base derivative.Moreover, the prodrug derivatives of this invention may be combined withother features herein taught to enhance bioavailability.

As mentioned above, the compounds of this invention find utility astherapeutic agents for disease states in mammals which have disorders ofcoagulation such as in the treatment or prevention of unstable angina,refractory angina, myocardial infarction, transient ischemic attacks,thrombotic stroke, embolic stroke, disseminated intravascularcoagulation including the treatment of septic shock, deep venousthrombosis in the prevention of pulmonary embolism or the treatment ofreocclusion or restenosis of reperfused coronary arteries. Further,these compounds are useful for the treatment or prophylaxis of thosediseases which involve the production and/or action of factorXa/prothrombinase complex. This includes a number of thrombotic andprothrombotic states in which the coagulation cascade is activated whichinclude but are not limited to, deep venous thrombosis, pulmonaryembolism, myocardial infarction, stroke, thromboembolic complications ofsurgery and peripheral arterial occlusion.

Accordingly, a method for preventing or treating a condition in a mammalcharacterized by undesired thrombosis comprises administering to themammal a therapeutically effective amount of a compound of thisinvention. In addition to the disease states noted above, other diseasestreatable or preventable by the administration of compounds of thisinvention include, without limitation, occlusive coronary thrombusformation resulting from either thrombolytic therapy or percutaneoustransluminal coronary angioplasty, thrombus formation in the venousvasculature, disseminated intravascular coagulopathy, a conditionwherein there is rapid consumption of coagulation factors and systemiccoagulation which results in the formation of life-threatening thrombioccurring throughout the microvasculature leading to widespread organfailure, hemorrhagic stroke, renal dialysis, blood oxygenation, andcardiac catheterization.

The compounds of the invention also find utility in a method forinhibiting the coagulation biological samples, which comprises theadministration of a compound of the invention.

The compounds of the present invention may also be used in combinationwith other therapeutic or diagnostic agents. In certain preferredembodiments, the compounds of this invention may be coadministered alongwith other compounds typically prescribed for these conditions accordingto generally accepted medical practice such as anticoagulant agents,thrombolytic agents, or other antithrombotics, including plateletaggregation inhibitors, tissue plasminogen activators, urokinase,prourokinase, streptokinase, heparin, aspirin, or warfarin. Thecompounds of the present invention may act in a synergistic fashion toprevent reocclusion following a successful thrombolytic therapy and/orreduce the time to reperfusion. These compounds may also allow forreduced doses of the thrombolytic agents to be used and thereforeminimize potential hemorrhagic side-effects. The compounds of thisinvention can be utilized in vivo, ordinarily in mammals such asprimates, (e.g. humans), sheep, horses, cattle, pigs, dogs, cats, ratsand mice, or in vitro.

The biological properties of the compounds of the present invention canbe readily characterized by methods that are well known in the art, forexample by the in vitro protease activity assays and in vivo studies toevaluate antithrombotic efficacy, and effects on hemostasis andhematological parameters, such as are illustrated in the examples.

Diagnostic applications of the compounds of this invention willtypically utilize formulations in the form of solutions or suspensions.In the management of thrombotic disorders the compounds of thisinvention may be utilized in compositions such as tablets, capsules orelixirs for oral administration, suppositories, sterile solutions orsuspensions or injectable administration, and the like, or incorporatedinto shaped articles. Subjects in need of treatment (typicallymammalian) using the compounds of this invention can be administereddosages that will provide optimal efficacy. The dose and method ofadministration will vary from subject to subject and be dependent uponsuch factors as the type of mammal being treated, its sex, weight, diet,concurrent medication, overall clinical condition, the particularcompounds employed, the specific use for which these compounds areemployed, and other factors which those skilled in the medical arts willrecognize.

Formulations of the compounds of this invention are prepared for storageor administration by mixing the compound having a desired degree ofpurity with physiologically acceptable carriers, excipients, stabilizersetc., and may be provided in sustained release or timed releaseformulations. Acceptable carriers or diluents for therapeutic use arewell known in the pharmaceutical field, and are described, for example,in Remington's Pharmaceutical Sciences, Mack Publishing Co., (A.R.Gennaro edit. 1985). Such materials are nontoxic to the recipients atthe dosages and concentrations employed, and include buffers such asphosphate, citrate, acetate and other organic acid salts, antioxidantssuch as ascorbic acid, low molecular weight (less than about tenresidues) peptides such as polyarginine, proteins, such as serumalbumin, gelatin, or immunoglobulins, hydrophilic polymers such aspolyvinylpyrrolidinone, amino acids such as glycine, glutamic acid,aspartic acid, or arginine, monosaccharides, disaccharides, and othercarbohydrates including cellulose or its derivatives, glucose, mannoseor dextrins, chelating agents such as EDTA, sugar alcohols such asmannitol or sorbitol, counterions such as sodium and/or nonionicsurfactants such as Tween, Pluronics or polyethyleneglycol.

Dosage formulations of the compounds of this invention to be used fortherapeutic administration must be sterile. Sterility is readilyaccomplished by filtration through sterile membranes such as 0.2 micronmembranes, or by other conventional methods. Formulations typically willbe stored in lyophilized form or as an aqueous solution. The pH of thepreparations of this invention typically will be 3-11, more preferably5-9 and most preferably 7-8. It will be understood that use of certainof the foregoing excipients, carriers, or stabilizers will result in theformation of cyclic polypeptide salts. While the preferred route ofadministration is by injection, other methods of administration are alsoanticipated such as orally, intravenously (bolus and/or infusion),subcutaneously, intramuscularly, colonically, rectally, nasally,transdermally or intraperitoneally, employing a variety of dosage formssuch as suppositories, implanted pellets or small cylinders, aerosols,oral dosage formulations and topical formulations such as ointments,drops and dermal patches. The compounds of this invention are desirablyincorporated into shaped articles such as implants which may employinert materials such as biodegradable polymers or synthetic silicones,for example, Silastic, silicone rubber or other polymers commerciallyavailable.

The compounds of the invention may also be administered in the form ofliposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles and multilamellar vesicles. Liposomes can be formedfrom a variety of lipids, such as cholesterol, stearylamine orphosphatidylcholines.

The compounds of this invention may also be delivered by the use ofantibodies, antibody fragments, growth factors, hormones, or othertargeting moieties, to which the compound molecules are coupled. Thecompounds of this invention may also be coupled with suitable polymersas targetable drug carriers. Such polymers can includepolyvinylpyrrolidinone, pyran copolymer,polyhydroxy-propyl-methacrylamide-phenol,polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, compounds of theinvention may be coupled to a class of biodegradable polymers useful inachieving controlled release of a drug, for example polylactic acid,polyglycolic acid, copolymers of polylactic and polyglycolic acid,polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacrylates and cross linked oramphipathic block copolymers of hydrogels. Polymers and semipermeablepolymer matrices may be formed into shaped articles, such as valves,stents, tubing, prostheses and the like.

Therapeutic compound liquid formulations generally are placed into acontainer having a sterile access port, for example, an intravenoussolution bag or vial having a stopper pierceable by hypodermic injectionneedle.

Therapeutically effective dosages may be determined by either in vitroor in vivo methods. For each particular compound of the presentinvention, individual determinations may be made to determine theoptimal dosage required. The range of therapeutically effective dosageswill be influenced by the route of administration, the therapeuticobjectives and the condition of the patient. For injection by hypodermicneedle, it may be assumed the dosage is delivered into the body'sfluids. For other routes of administration, the absorption efficiencymust be individually determined for each compound by methods well knownin pharmacology. Accordingly, it may be necessary for the therapist totiter the dosage and modify the route of administration as required toobtain the optimal therapeutic effect. The determination of effectivedosage levels, that is, the dosage levels necessary to achieve thedesired result, will be readily determined by one skilled in the art.Typically, applications of compound are commenced at lower dosagelevels, with dosage levels being increased until the desired effect isachieved.

The compounds of the invention can be administered orally orparenterally in an effective amount within the dosage range of about 0.1to 100 mg/kg, preferably about 0.5 to 50 mg/kg and more preferably about1 to 20 mg/kg on a regimen in a single or 2 to 4 divided daily dosesand/or continuous infusion.

Typically, about 5 to 500 mg of a compound or mixture of compounds ofthis invention, as the free acid or base form or as a pharmaceuticallyacceptable salt, is compounded with a physiologically acceptablevehicle, carrier, excipient, binder, preservative, stabilizer, dye,flavor etc., as called for by accepted pharmaceutical practice. Theamount of active ingredient in these compositions is such that asuitable dosage in the range indicated is obtained.

Typical adjuvants which may be incorporated into tablets, capsules andthe like are binders such as acacia, corn starch or gelatin, andexcipients such as microcrystalline cellulose, disintegrating agentslike corn starch or alginic acid, lubricants such as magnesium stearate,sweetening agents such as sucrose or lactose, or flavoring agents. Whena dosage form is a capsule, in addition to the above materials it mayalso contain liquid carriers such as water, saline, or a fatty oil.Other materials of various types may be used as coatings or as modifiersof the physical form of the dosage unit. Sterile compositions forinjection can be formulated according to conventional pharmaceuticalpractice. For example, dissolution or suspension of the active compoundin a vehicle such as an oil or a synthetic fatty vehicle like ethyloleate, or into a liposome may be desired. Buffers, preservatives,antioxidants and the like can be incorporated according to acceptedpharmaceutical practice.

Preparation of Compounds

The compounds of the present invention may be synthesized by eithersolid or liquid phase methods described and referenced in standardtextbooks, or by a combination of both methods. These methods are wellknown in the art. See, Bodanszky, “The Principles of Peptide Synthesis”,Hafner, et al., Eds., Springer-Verlag, Berlin, 1984.

Starting materials used in any of these methods are commerciallyavailable from chemical vendors such as Aldrich, Sigma, NovaBiochemicals, Bachem Biosciences, and the like, or may be readilysynthesized by known procedures.

Reactions are carried out in standard laboratory glassware and reactionvessels under reaction conditions of standard temperature and pressure,except where otherwise indicated.

During the synthesis of these compounds, the functional groups of theamino acid derivatives used in these methods are protected by blockinggroups to prevent cross reaction during the coupling procedure. Examplesof suitable blocking groups and their use are described in “ThePeptides: Analysis, Synthesis, Biology”, Academic Press, Vol. 3 (Gross,et al., Eds., 1981) and Vol. 9 (1987), the disclosures of which areincorporated herein by reference.

Compounds according to the invention can be synthesized utilizingprocedures well known in the art. The reaction products are isolated andpurified by conventional methods, typically by solvent extraction into acompatible solvent. The products may be further purified by columnchromatography or other appropriate methods.

Compositions and Formulations

The compounds of this invention may be isolated as the free acid or baseor converted to salts of various inorganic and organic acids and bases.Such salts are within the scope of this invention. Non-toxic andphysiologically compatible salts are particularly useful although otherless desirable salts may have use in the processes of isolation andpurification.

A number of methods are useful for the preparation of the saltsdescribed above and are known to those skilled in the art. For example,reaction of the free acid or free base form of a compound of thestructures recited above with one or more molar equivalents of thedesired acid or base in a solvent or solvent mixture in which the saltis insoluble, or in a solvent like water after which the solvent isremoved by evaporation, distillation or freeze drying. Alternatively,the free acid or base form of the product may be passed over an ionexchange resin to form the desired salt or one salt form of the productmay be converted to another using the same general process.

Diagnostic applications of the compounds of this invention willtypically utilize formulations such as solution or suspension. In themanagement of thrombotic disorders the compounds of this invention maybe utilized in compositions such as tablets, capsules or elixirs fororal administration, suppositories, sterile solutions or suspensions orinjectable administration, and the like, or incorporated into shapedarticles. Subjects in need of treatment (typically mammalian) using thecompounds of this invention can be administered dosages that willprovide optimal efficacy. The dose and method of administration willvary from subject to subject and be dependent upon such factors as thetype of mammal being treated, its sex, weight, diet, concurrentmedication, overall clinical condition, the particular compoundsemployed, the specific use for which these compounds are employed, andother factors which those skilled in the medical arts will recognize.

Formulations of the compounds of this invention are prepared for storageor administration by mixing the compound having a desired degree ofpurity with physiologically acceptable carriers, excipients, stabilizersetc., and may be provided in sustained release or timed releaseformulations. Acceptable carriers or diluents for therapeutic use arewell known in the pharmaceutical field, and are described, for example,in Remington's Pharmaceutical Sciences, Mack Publishing Co., (A.R.Gennaro edit. 1985). Such materials are nontoxic to the recipients atthe dosages and concentrations employed, and include buffers such asphosphate, citrate, acetate and other organic acid salts, antioxidantssuch as ascorbic acid, low molecular weight (less than about tenresidues) peptides such as polyarginine, proteins, such as serumalbumin, gelatin, or immunoglobulins, hydrophilic polymers such aspolyvinalpyrrolidinone, amino acids such as glycine, glutamic acid,aspartic acid, or arginine, monosaccharides, disaccharides, and othercarbohydrates including cellulose or its derivatives, glucose, mannoseor dextrins, chelating agents such as EDTA, sugar alcohols such asmannitol or sorbitol, counterions such as sodium and/or nonionicsurfactants such as Tween, Pluronics or polyethyleneglycol.

Dosage formulations of the compounds of this invention to be used fortherapeutic administration must be sterile. Sterility is readilyaccomplished by filtration through sterile membranes such as 0.2 micronmembranes, or by other conventional methods. Formulations typically willbe stored in lyophilized form or as an aqueous solution. The pH of thepreparations of this invention typically will be between 3 and 11, morepreferably from 5 to 9 and most preferably from 7 to 8. It will beunderstood that use of certain of the foregoing excipients, carriers, orstabilizers will result in the formation of cyclic polypeptide salts.While the preferred route of administration is by injection, othermethods of administration are also anticipated such as intravenously(bolus and/or infusion), subcutaneously, intramuscularly, colonically,rectally, nasally or intraperitoneally, employing a variety of dosageforms such as suppositories, implanted pellets or small cylinders,aerosols, oral dosage formulations and topical formulations such asointments, drops and dermal patches. The compounds of this invention aredesirably incorporated into shaped articles such as implants which mayemploy inert materials such as biodegradable polymers or syntheticsilicones, for example, Silastic, silicone rubber or other polymerscommercially available.

The compounds of this invention may also be administered in the form ofliposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles and multilamellar vesicles. Liposomes can be formedfrom a variety of lipids, such as cholesterol, stearylamine orphosphatidylcholines.

The compounds of this invention may also be delivered by the use ofantibodies, antibody fragments, growth factors, hormones, or othertargeting moieties, to which the compound molecules are coupled. Thecompounds of this invention may also be coupled with suitable polymersas targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxy-propyl-methacrylamide-phenol,polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the factor Xainhibitors of this invention may be coupled to a class of biodegradablepolymers useful in achieving controlled release of a drug, for examplepolylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross linked or amphipathic block copolymers of hydrogels. Polymers andsemipermeable polymer matrices may be formed into shaped articles, suchas valves, stents, tubing, prostheses and the like.

Therapeutic compound liquid formulations generally are placed into acontainer having a sterile access port, for example, an intravenoussolution bag or vial having a stopper pierceable by hypodermic injectionneedle.

Therapeutically effective dosages may be determined by either in vitroor in vivo methods. For each particular compound of the presentinvention, individual determinations may be made to determine theoptimal dosage required. The range of therapeutically effective dosageswill naturally be influenced by the route of administration, thetherapeutic objectives, and the condition of the patient. For injectionby hypodermic needle, it may be assumed the dosage is delivered into thebody's fluids. For other routes of administration, the absorptionefficiency must be individually determined for each inhibitor by methodswell known in pharmacology. Accordingly, it may be necessary for thetherapist to titer the dosage and modify the route of administration asrequired to obtain the optimal therapeutic effect. The determination ofeffective dosage levels, that is, the dosage levels necessary to achievethe desired result, will be within the ambit of one skilled in the art.Typically, applications of compound are commenced at lower dosagelevels, with dosage levels being increased until the desired effect isachieved.

A typical dosage might range from about 0.001 mg/kg to about 1000 mg/kg,preferably from about 0.01 mg/kg to about 100 mg/kg, and more preferablyfrom about 0.10 mg/kg to about 20 mg/kg. Advantageously, the compoundsof this invention may be administered several times daily, and otherdosage regimens may also be useful.

Typically, about 0.5 to 500 mg of a compound or mixture of compounds ofthis invention, as the free acid or base form or as a pharmaceuticallyacceptable salt, is compounded with a physiologically acceptablevehicle, carrier, excipient, binder, preservative, stabilizer, dye,flavor etc., as called for by accepted pharmaceutical practice. Theamount of active ingredient in these compositions is such that asuitable dosage in the range indicated is obtained.

Typical adjuvants which may be incorporated into tablets, capsules andthe like are a binder such as acacia, corn starch or gelatin, andexcipient such as microcrystalline cellulose, a disintegrating agentlike corn starch or alginic acid, a lubricant such as magnesiumstearate, a sweetening agent such as sucrose or lactose, or a flavoringagent. When a dosage form is a capsule, in addition to the abovematerials it may also contain a liquid carrier such as water, saline, afatty oil. Other materials of various types may be used as coatings oras modifiers of the physical form of the dosage unit. Sterilecompositions for injection can be formulated according to conventionalpharmaceutical practice. For example, dissolution or suspension of theactive compound in a vehicle such as an oil or a synthetic fatty vehiclelike ethyl oleate, or into a liposome may be desired. Buffers,preservatives, antioxidants and the like can be incorporated accordingto accepted pharmaceutical practice.

In practicing the methods of this invention, the compounds of thisinvention may be used alone or in combination, or in combination withother therapeutic or diagnostic agents. In certain preferredembodiments, the compounds of this inventions may be coadministeredalong with other compounds typically prescribed for these conditionsaccording to generally accepted medical practice, such as anticoagulantagents, thrombolytic agents, or other antithrombotics, includingplatelet aggregation inhibitors, tissue plasminogen activators,urokinase, prourokinase, streptokinase, heparin, aspirin, or warfarin.The compounds of this invention can be utilized in vivo, ordinarily inmammals such as primates, such as humans, sheep, horses, cattle, pigs,dogs, cats, rats and mice, or in vitro.

The preferred compounds of the present invention are characterized bytheir ability to inhibit thrombus formation with acceptable effects onclassical measures of coagulation parameters, platelets and plateletfunction, and acceptable levels of bleeding complications associatedwith their use. Conditions characterized by undesired thrombosis wouldinclude those involving the arterial and venous vasculature.

With respect to the coronary arterial vasculature, abnormal thrombusformation characterizes the rupture of an established atheroscleroticplaque which is the major cause of acute myocardial infarction andunstable angina, as well as also characterizing the occlusive coronarythrombus formation resulting from either thrombolytic therapy orpercutaneous transluminal coronary angioplasty (PTCA).

With respect to the venous vasculature, abnormal thrombus formationcharacterizes the condition observed in patients undergoing majorsurgery in the lower extremities or the abdominal area who often sufferfrom thrombus formation in the venous vasculature resulting in reducedblood flow to the affected extremity and a predisposition to pulmonaryembolism. Abnormal thrombus formation further characterizes disseminatedintravascular coagulopathy commonly occurs within both vascular systemsduring septic shock, certain viral infections and cancer, a conditionwherein there is rapid consumption of coagulation factors and systemiccoagulation which results in the formation of life-threatening thrombioccurring throughout the microvasculature leading to widespread organfailure.

The compounds of this present invention, selected and used as disclosedherein, are believed to be useful for preventing or treating a conditioncharacterized by undesired thrombosis, such as (a) the treatment orprevention of any thrombotically mediated acute coronary syndromeincluding myocardial infarction, unstable angina, refractory angina,occlusive coronary thrombus occurring post-thrombolytic therapy orpost-coronary angioplasty, (b) the treatment or prevention of anythrombotically mediated cerebrovascular syndrome including embolicstroke, thrombotic stroke or transient ischemic attacks, (c) thetreatment or prevention of any thrombotic syndrome occurring in thevenous system including deep venous thrombosis or pulmonary embolusoccurring either spontaneously or in the setting of malignancy, surgeryor trauma, (d) the treatment or prevention of any coagulopathy includingdisseminated intravascular coagulation (including the setting of septicshock or other infection, surgery, pregnancy, trauma or malignancy andwhether associated with multi-organ failure or not), thromboticthrombocytopenic purpura, thromboangiitis obliterans, or thromboticdisease associated with heparin induced thrombocytopenia, (e) thetreatment or prevention of thrombotic complications associated withextracorporeal circulation (e.g. renal dialysis, cardiopulmonary bypassor other oxygenation procedure, plasmapheresis), (f) the treatment orprevention of thrombotic complications associated with instrumentation(e.g. cardiac or other intravascular catheterization, intra-aorticballoon pump, coronary stent or cardiac valve), and (g) those involvedwith the fitting of prosthetic devices.

Anticoagulant therapy is also useful to prevent coagulation of storedwhole blood and to prevent coagulation in other biological samples fortesting or storage. Thus the compounds of this invention can be added toor contacted with any medium containing or suspected to contain factorXa and in which it is desired that blood coagulation be inhibited, e.g.,when contacting the mammal's blood with material such as vasculargrafts, stents, orthopedic prostheses, cardiac stents, valves andprostheses, extra corporeal circulation systems and the like.

Without further description, it is believed that one of ordinary skillin the art can, using the preceding description and the followingillustrative examples, make and utilize the compounds of the presentinvention and practice the claimed methods.

EXAMPLES Examples of Chemical Production Process General ReactionSchemes

Example 1N-(5-bromo-2-pyridinyl)-(2-4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenylcarboxamide

Step 1: A solution of 2-nitrobenzoyl chloride (3.70 g, 20 mmol, 1.0equiv), 2-amino-5-bromopyridine (3.50 g, 1.0 equiv), pyridine (10 mL) in25 mL of methylene chloride was stirred overnight. The volatile wasevaporated, flash chromatography on silica gel gaveN-(5-bromo-2-pyridinyl)-(2-nitro)phenylcarboxamide (5.02 g, 77%). MSfound for C₁₂H₉BrN₃O₃ (M+H)⁺: 322.

Step 2: A solution of N-(5-bromo-2-pyridinyl)-(2-nitro)phenylcarboxamide(1.0 g, 3.1 mmol, 1.0 equiv) in 30 mL of EtOAc was treated withSnCl₂.2H₂O (2.80 g, 4 equiv) at reflux for 4 h. The volatile wasevaporated and the residue was redissolved in EtOAc, washed withsaturated aqueous NaHCO₃ and 1N NaOH. The organic layer was dried overMgSO₄, filtered and evaporated toN-(5-bromo-2-pyridinyl)-(2-amino)phenylcarboxamide (0.89 g, 98%). MSfound for C₁₂H₁₁BrN₃O (M+H)⁺: 292.

Step 3: A mixture of N-(5-bromo-2-pyridinyl)-(2-amino)phenylcarboxamide(292 mg, 1 mmol, 1.0 equiv), 4-[(2-t-butylaminosulfonyl)phenyl]benzoylchloride (349 mg, 1 equiv), pyridine (3 mL) in 10 mL of dichloromethanewas stirred at rt overnight, washed with H₂O. The organic layer wasdried over MgSO₄, filtered, evaporated and refluxed in 2 mL oftrifluoroacetic acid for 30 min. TFA was then evaporated and HPLC (C18reversed phase) eluting with 0.5% TFA in H₂O/CH₃CN gaveN-(5-bromo-2-pyridinyl)-(2-4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenylcarboxamide(470 mg, 85%). MS found for C₂₅H₂₀BrN₄O₄S (M+H)⁺: 551.

Example 2N-(5-chloro-2-pyridinyl)-(2-4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenylcarboxamide

A mixture of N-(5-chloro-2-pyridinyl)-(2-amino)phenylcarboxamide (247mg, 1 mmol, 1.0 equiv), 4-[(2-t-butylaminosulfonyl)phenyl]benzoylchloride (349 mg, 1 equiv), pyridine (3 mL) in 10 mL of dichloromethanewas stirred at rt overnight, washed with H₂O. The organic layer wasdried over MgSO₄, filtered, evaporated and refluxed in 2 mL oftrifluoroacetic acid for 30 min. TFA was then evaporated and HPLC (C18reversed phase) eluting with 0.5% TFA in H₂O/CH₃CN gaveN-(5-chloro-2-pyridinyl)-(2-4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenylcarboxamide(370 mg, 73%). MS found for C₂₅H₂₀ClN₄O₄S (M+H)⁺: 507.

Example 3N-(5-bromo-2-pyridinyl)-(2-(4-[(2-methylsulfonyl)phenyl]phenylcarbonyl)amino)phenylcarboxamide

Step 1: To a mixture of 2-bromothioanisole (4.8 g, 23.6 mmol),4-carboxybenzeneboronic acid (3.92 g, 23.6 mmol) and 2M K₂CO₃ (35.5mmol, 71 mmol) in dioxane (20 ml) was addeddichlorobis(triphenylphosphine)palladium (II) (415 mg, 0.6 mmol) underAr. It was refluxed for 2 hrs. After the removal of the solvent, theresidue was neutralized by 1N HCl and extracted with dichloromethane.The organic layer was dried over MgSO₄ and concentrated in vacuo to give4-[(2-methylthio)phenyl]benzoic acid (5.9 g, 100%). ES-MS (M+H)⁺=245.

Step 2: To a solution of 4[(2-methylthio)phenyl]benzoic acid (3.43 g, 14mmol) in H₂O (10 ml) and acetone (20 ml) was added oxone monopersulfate(34.6 g, 56 mmol). The mixture was stirred at r.t. overnight. After theremoval of the solvent, the residue was extracted with ethyl acetate.The organic layer was dried over MgSO₄ and concentrated in vacuo to give2.16 g (63%) 4[(2-methylsulfonyl)phenyl]benzoic acid. ES-MS (M+H)⁺=277.

Step 3: To a solution of 4[(2-methylsulfonyl)phenyl]benzoic acid (552mg, 2 mmol) in dichloromethane (5 ml) was added oxalyl chloride (350 ul,4 mmol) and 2 drops of DMF. The mixture was stirred at r.t. for 2 hrs.After the removal of the solvent in vacuo, the residue was dissolved indichloromethane (5 ml),N-(5-bromo-2-pyridinyl)-(2-amino)phenylcarboxamide (700 mg, 2.4 mmol),pyridine (486 ul, 6 mmol) and catalytic amount of DMAP were added. Themixture was stirred at r.t. overnight. After the removal of the solvent,the residue was purified by flash column (30% ethyl acetate/hexane) andthen preparative HPLC to get 414 mg (38%) ofN-(5-bromo-2-pyridinyl)-(2-(4-[(2-methylsulfonyl)phenyl]phenylcarbonyl)amino)phenylcarboxamide.ES-MS M⁺=550, (M+2)⁺=552.

Example 4N-(5-chloro-2-pyridinyl)-(2-(4-[(2-methylsulfonyl)phenyl]phenylcarbonyl)amino)phenylcarboxamide

To a solution of 4[(2-methylsulfonyl)phenyl]benzoic acid (280 mg, 1mmol) in dichloromethane (5 ml) was added oxalyl chloride (175 ul, 2mmol) and 2 drops of DMF. The mixture was stirred at r.t. for 2 hrs.After the removal of the solvent in vacuo, the residue was dissolved indichloromethane (5 ml),N-(5-chloro-2-pyridinyl)-(2-amino)phenylcarboxamide (297 mg, 1.2 mmol),pyridine (243 ul, 3 mmol) and catalytic amount of DMAP were added. Themixture was stirred at r.t. overnight. After the removal of the solvent,the residue was purified by flash column (30% ethyl acetate/hexane) andthen preparative HPLC to get 95 mg (20%) ofN-(5-chloro-2-pyridinyl)-(2-(4-[(2-methylsulfonyl)phenyl]phenylcarbonyl)amino)phenylcarboxamide.ES-MS M⁺=505.5, (M+2)⁺=507.5.

Example 5N-(4-bromo-2-methoxycarbonyphenyl)-(2-(4-[(2-methylsulfonyl)phenyl]phenylcarbonyl)amino)phenylcarboxamide

A sample of 4[(2-methylsulfonyl)phenyl]benzoic acid (280 mg, 1 mmol, 1equiv) was refluxed with 2 mL of thionyl chloride for 2 h andevaporated. The residue was dissolved in 5 mL of dichloromethane,N-(4-bromo-2-methoxycarbonyphenyl)-(2-amino)phenylcarboxamide (348 mg, 1equiv), pyridine (3 mL) were added. The mixture was stirred at r.t.overnight. After the removal of the solvent, the residue was purified byflash column to give 480 mg (79%) ofN-(4-bromo-2-methoxycarbonyphenyl)-(2-(4-[(2-methylsulfonyl)phenyl]phenylcarbonyl)amino)phenylcarboxamide.MS found for C₂₉H₂₄BrN₂O₆S (M+H)⁺: 607.

Example 6N-(4-chloro-2-methoxycarbonyphenyl)-(2-(4-[(2-methylsulfonyl)phenyl]phenylcarbonyl)amino)phenylcarboxamide

A sample of 4[(2-methylsulfonyl)phenyl]benzoic acid (280 mg, 1 mmol, 1equiv) was refluxed with 2 mL of thionyl chloride for 2 h andevaporated. The residue was dissolved in 5 mL of dichloromethane,N-(4-chloro-2-methoxycarbonyphenyl)-(2-amino)phenylcarboxamide (304 mg,1 equiv), pyridine (3 mL) were added. The mixture was stirred at r.t.overnight. After the removal of the solvent, the residue was purified byflash column to give 479 mg (85%) ofN-(4-chloro-2-methoxycarbonyphenyl)-(2-(4-[(2-methylsulfonyl)phenyl]phenylcarbonyl)amino)phenylcarboxamide.MS found for C₂₉H₂₄ClN₂O₆S (M+H)⁺: 563.

Example 7N-(5-bromo-2-pyridinyl)-(2-4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)pyridinyl-3-carboxamide

Step 1: A solution of 2-aminopyridine-3-carboxylic acid (138 mg, 1 mmol)in 10 mL of methanol was treated with thionyl chloride in portions untilcomplete reaction. The solvent was evaporated and the residue wasdissolved in 10 mL of pyridine. To the solution were added4-[(2-t-butylaminosulfonyl)-phenyl]benzoic acid and POCl₃. The resultingmixture was stirred at rt overnight, quenched by slow addition of water,and extracted with EtOAc. The organic layer was dried over MgSO₄,filtered and flash chromatographied to give methyl2-(4-[(2-t-butylaminosulfonyl)-phenyl]phenylcarbonyl)-aminopyridine-3-carboxylate(243 mg, 52%). MS found for C₂₄H₂₆N₃O₅S (M+H)⁺: 468.

Step 2: To A solution of 2-amino-5-bromopridine (45 mg, 4.0 equiv) in 5mL of methylene chloride treated with AlMe₃ (2M in hexane, 0.65 mL, 20equiv) for 30 min was added methyl2-(4-[(2-t-butylaminosulfonyl)-phenyl]phenylcarbonyl)-aminopyridine-3-carboxylate(30 mg, 0.064 mmol, 1 equiv). The mixture was stirred at rt overnight,quenched with saturated aqueous potassium sodium tartrate. The organiclayer was dried over MgSO₄, filtered, evaporated and refluxed in 2 mL oftrifluoroacetic acid for 30 min TFA was then evaporated and HPLC (C18reversed phase) eluting with 0.5% TFA in H₂O/CH₃CN gaveN-(5-bromo-2-pyridinyl)-(2-4-[(2-aminosulfonyl)-phenyl]phenylcarbonylamino)pyridinyl-3-carboxamide(17 mg, 48%). MS found for C₂₄H₁₉BrN₅O₄S (M+H)⁺: 552.

Example 8N-(5-chloro-2-pyridinyl)-(2-4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)pyridinyl-3-carboxamide

To A solution of 2-amino-5-chloropridine (32 mg, 4.0 equiv) in 5 mL ofmethylene chloride treated with AlMe₃ (2M in hexane, 0.65 mL, 20 equiv)for 30 min was added methyl2-(4-[(2-t-butylaminosulfonyl)-phenyl]phenylcarbonyl)-aminopyridine-3-carboxylate(30 mg, 0.064 mmol, 1 equiv). The mixture was stirred at rt overnight,quenched with saturated aqueous potassium sodium tartrate. The organiclayer was dried over MgSO₄, filtered, evaporated and refluxed in 2 mL oftrifluoroacetic acid for 30 min. TFA was then evaporated and HPLC (C18reversed phase) eluting with 0.5% TFA in H₂O/CH₃CN gaveN-(5-chloro-2-pyridinyl)-(2-4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)pyridinyl-3-carboxamide(21 mg, 66%). MS found for C₂₄H₁₉ClN₅O₄S (M+H)⁺: 508.

Example 9N-(5-bromo-2-pyridinyl)-(3-4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)pyridinyl-2-carboxamide

To A solution of 2-amino-5-bromopridine (69.2 mg, 4.0 equiv) in 5 mL ofmethylene chloride treated with AlMe₃ (2M in hexane, 1 mL, 20 equiv) for30 min was added3-(4-[(2-t-butylaminosulfonyl)phenyl]phenylcarbonyl)aminopyridine-2-carboxylate(46.7 mg, 1 equiv). The mixture was stirred at rt overnight, quenchedwith saturated aqueous potassium sodium tartrate. The organic layer wasdried over MgSO₄, filtered, evaporated and refluxed in 2 mL oftrifluoroacetic acid for 30 min. TFA was then evaporated and HPLC (C18reversed phase) eluting with 0.5% TFA in H₂O/CH₃CN gaveN-(5-bromo-2-pyridinyl)-(3-4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)pyridinyl-2-carboxamide(29 mg, 53%). MS found for C₂₄H₁₉BrN₅O₄S (M+H)⁺: 552.

Example 10N-(5-chloro-2-pyridinyl)-(2-4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)pyridinyl-3-carboxamide

To A solution of 2-amino-5-chloropridine (51.2 mg, 4.0 equiv) in 5 mL ofmethylene chloride treated with AlMe₃ (2M in hexane, 1 mL, 20 equiv) for30 min was added3-(4-[(2-t-butylaminosulfonyl)phenyl]phenylcarbonyl)aminopyridine-2-carboxylate(46.7 mg, 0.1 mmol, 1 equiv). The mixture was stirred at rt overnight,quenched with saturated aqueous potassium sodium tartrate. The organiclayer was dried over MgSO₄, filtered, evaporated and refluxed in 2 mL oftrifluoroacetic acid for 30 min TFA was then evaporated and HPLC (C18reversed phase) eluting with 0.5% TFA in H₂O/CH₃CN gaveN-(5-chloro-2-pyridinyl)-(2-4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)pyridinyl-3-carboxamide(33 mg, 64%). MS found for C₂₄H₁₉ClN₅O₄S (M+H)⁺: 508.

Examples 11-14

The following compounds were prepared using the procedure describedpreviously:

Example 15N-(4-bromo-2-nitrophenyl)-(2-(4-[(2-methylsulfonyl)phenyl]phenylcarbonyl)amino)phenylcarboxamide

Step 1: A mixture of methyl 2-aminobenzoate (150 mg, 1 mmol, 1.0 equiv),4-[(2-methylsulfonyl)phenyl]benzoic chloride (294 mg, 1 equiv), pyridine(3 mL) in 10 mL of dichloromethane was stirred at rt overnight, washedwith H₂O. The organic layer was dried over MgSO₄, filtered andevaporated. Flash chromatography on silica gel gave methyl2-(4[(2-methylsulfonyl)phenyl]phenylcarbonyl)aminobenzoate (250 mg,54%). MS found for C₂₅H₂₇N₂O₅S (M+H)⁺: 467.

Step 2: To a solution of 4-bromo-2-nitroaniline (43.4 mg, 0.2 mmol, 2.0equiv) in 5 mL of methylene chloride treated with AlMe₃ (2M in hexane,0.3 mL, 6 equiv) for 30 min was added methyl2-(4[(2-methylsulfonyl)phenyl]phenylcarbonyl)aminobenzoate (46.6 mg, 1equiv). The mixture was stirred at rt overnight, quenched with saturatedaqueous potassium sodium tartrate. The organic layer was dried overMgSO₄, filtered and evaporated. Flash chromatography on silica gel gaveN-(4-bromo-2-nitrophenyl)-(2-(4-[(2-methylsulfonyl)phenyl]phenylcarbonyl)amino)phenylcarboxamide(5 mg, 9%). MS found for C₂₇H₂₁BrN₃O₆S (M+H)⁺: 594.

Example 16N-(4-methoxyphenyl)-N′-(4-[(2-aminosulfonyl)phenyl]phenyl)-maleamicamide

A. Preparation ofN-(4-methoxyphenyl)-N′-(4-[(2-tert-butylaminosulfonyl)phenyl]phenyl)-maleamicamide

To a solution of commercially available N-(4-methoxyphenyl)maleamic acid(100 mg, 0.452 mmol), triethylamine (0.126 mL, 0.906 mmol) and4-(2-tert-butylaminosulfonylphenyl)aniline (138 mg, 0.454 mmol) inanhydrous DMF (5 mL), BOP (260 mg, 0.588 mmol) was added. The mixturewas stirred at room temperature overnight. Water and EtOAc were added.The organic phase was separated, washed with H2O, then with 5% NaHCO3,dried over Na2SO4, concentrated in vacuo. The residue was purified byHPLC using a gradient of 20% CH3CN in H2O (containing 0.1% TFA) to 100%CH3CN over 80 min. Fractions containing the desired product were pooled,and lyophilized to give a powder (70 mg, yield: 31%). MS 508 (M+H).

B. Preparation ofN-(4-methoxyphenyl)-N′-(4-[(2-aminosulfonyl)phenyl]phenyl)-maleamicamide

The compoundN-(4-methoxyphenyl)-N′-(4-[(2-tert-butylaminosulfonyl)phenyl]phenyl)-maleamicamide (40 mg, 79 mol) was dissolved in TFA (3 mL). It was allowed tostand at room temperature overnight. TFA was removed in vacuo. Theresidue was purified by HPLC using a gradient of 5% CH3CN in H2O(containing 0.1% TFA) to 95% CH3CN over 60 min. Fractions containing thedesired product were pooled, and lyophilized to give a powder (18 mg,yield: 51%). MS 452 (M+H) and 474 (M+Na). ¹H NMR (CDCl3) δ 11.40 (br.s,1H), 10.28 (br.s, 1H), 8.12 (d, 1H, J=8 Hz), 7.72 (d, 2H, J=8 Hz),7.60-7.20 (m, 9H), 6.86 (AB type, 2H), 6.45 (br.s, 2H), 3.79 (s, 3H).

Example 17N-(4-bromophenyl)-N′-(4-[(2-aminosulfonyl)phenyl]phenyl)-maleamic amide

A. Preparation of N-(4[(2-tert-butylaminosulfonyl)phenyl]phenyl)maleamicmethyl ester

To a solution of commercially available maleic acid monomethyl ester(277 mg, 2.13 mmol), 4-(2-tert-butylaminosulfonylphenyl)aniline (648 mg,2.13 mmol) and triethylamine (0.593 mL, 4.26 mmol) in CH2Cl2 (20 mL),BOP (1.13 g, 2.55 mmol) was added. The mixture was stirred at roomtemperature overnight. More maleic acid monomethyl ester (50 mg, 0.385mmol) was added. It was stirred for 3 hours. The CH2Cl2 solution wasthen washed with sat. NaHCO3, 1N HCl and sat. NaCl. The solution wasdried over Na2SO4, concentrated in vacuo. The residue was purified by asilica gel column using a gradient of 10-40% EtOAc in hexane assolvents, to give the titled compound (360 mg, yield: 41%). MS 361(M+H-^(t)Bu) and 439 (M+Na).

B. Preparation ofN-(4-bromophenyl)-N′-(4-[(2-aminosulfonyl)phenyl]phenyl)-maleamic amide

To a solution of 4-bromoaniline (93 mg, 0.543 mmol) in CH2Cl2 (5 mL) atroom temperature, trimethylaluminum (0.82 mL, 2.0 M in hexane, 1.64mmol) was added dropwise. After the solution was stirred for 30 min atroom temperature, compoundN-(4[(2-tert-butylaminosulfonyl)phenyl]phenyl)maleamic methyl ester (113mg, 0.272 mmol) was added. The mixture was stirred at room temperaturefor 2 days. The solution was neutralized with 1N HCl to pH 2-3. Waterand CH2Cl2 were added, and organic phase was separated, dried overNa2SO4, concentrated in vacuo. The residue was dissolved in TFA (4 mL).It was allowed to stand at room temperature overnight. TFA was removedin vacuo. The residue was purified by HPLC using a gradient of 5% CH3CNin H2O (containing 0.1% TFA) to 95% CH3CN over 60 min. Fractionscontaining the desired product were pooled, and lyophilized to give apowder (8 mg, yield: 6%). MS 500 and 502 (M+H), 522 and 524 (M+Na). ¹HNMR (CD3OD) δ 8.09 (d, 1H, J=8 Hz), 7.68 (d, 2H, J=8 Hz), 7.64-7.28 (m,9H), 6.45 (AB type, 2H).

Examples 18 and 19 Preparation ofN¹-(5-bromopyridin-2-yl)-N⁴-(4-[(2-aminosulfonyl)phenyl]phenyl)-2-methylmaleamicamide andN¹-(5-bromopyridin-2-yl)-N⁴-(4-[(2-aminosulfonyl)phenyl]phenyl)-3-methylmaleamicamide

A. Preparation of N-(5-bromopyridin-2-yl)-methylmaleimide

A mixture of citraconic anhydride (1.00 mL, 11.1 mmol) and2-amino-5-bromopyridine (1.93 g, 11.2 mmol) in toluene (60 mL) washeated to reflux overnight. The solution was cooled down, filtered. Thefiltrate was concentrated in vacuo to give a solid (2.10 g, yield: 71%).MS 267 and 269 (M+H).

B. Preparation ofN¹-(5-bromopyridin-2-yl)-N⁴-(4-[(2-aminosulfonyl)phenyl]phenyl)-2-methylmaleamicamide andN¹-(5-bromopyridin-2-yl)-N⁴-(4-[(2-aminosulfonyl)phenyl]phenyl)-3-methylmaleamicamide

To the solution of 4-(2-aminosulfonylphenyl)aniline (0.170 g, 0.685mmol) in CH2Cl2 (10 mL) at room temperature, trimethylaluminum (2.0 M inhexane, 2.00 mL, 4.00 mmol) was added dropwise, during which time, whitegel-like precipitates came out the solution. It was stirred for 30 min.A solution of N-(5-bromopyridin-2-yl)-methylmaleimide (0.122 g, 0.457mmol) in CH2Cl2 (5 mL) was added. It was stirred for 1 hour, duringwhich time the precipitates started to dissolve, and the solution becameclear. It was stirred for another 2 hours. 1N HCl was added toneutralize the solution to pH 2-3, which resulted in precipitation. Theprecipitates were collected by filtration, dried on vacuum. Theprecipitates (75 mg, yield: 32%) were a mixture of 2-methyl and3-methylmaleamic amide isomers in a ratio of 1:5. MS 515 and 517 (M+H),537 and 539 (M+Na).

Example 20N-(5-bromo-2-pyridinyl)-(2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonyl)amino)-4-nitrophenylcarboxamide

Step 1: A solution of 2-amino-4-nitrobenzoic acid (182 mg, 1 mmol, 1equiv) in 10 mL of methanol was treated with thionyl chloride inportions until complete reaction. The solvent was evaporated and theresidue was dissolved in 10 mL of pyridine. To the solution were added4-[(2-t-butylaminosulfonyl)phenyl]benzoic acid (330 mg, 1 equiv) andPOCl₃ (0.93 mL, 10 equiv). The resulting mixture was stirred at rtovernight, quenched by slow addition of water, and extracted with EtOAc.The organic layer was dried over MgSO₄, filtered and flashchromatographied to give methyl2-(4-[(2-t-butylaminosulfonyl)phenyl]phenylcarbonyl)amino-4-nitrobenzoate(430 mg, 84%). MS found for C₂₅H₂₆N₃O₇S (M+H)⁺: 512.

Step 2: To A solution of 2-amino-5-bromopridine (135 mg, 4.0 equiv) in 5mL of methylene chloride treated with AlMe₃ (2M in hexane, 1 mL, 10equiv) for 30 min was added methyl2-(4-[(2-t-butylaminosulfonyl)phenyl]phenylcarbonyl)amino-4-nitrobenzoate(100 mg, 0.2 mmol, 1 equiv). The mixture was stirred at rt overnight,quenched with saturated aqueous potassium sodium tartrate. The organiclayer was dried over MgSO₄, filtered, evaporated and refluxed in 2 mL oftrifluoroacetic acid for 30 min. TFA was then evaporated and HPLC (C18reversed phase) eluting with 0.5% TFA in H₂O/CH₃CN gaveN-(5-bromo-2-pyridinyl)-(2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonyl)amino)-4-nitrophenylcarboxamide(42 mg, 36%). MS found for C₂₅H₁₉BrN₅O₆S (M+H)⁺: 596.

Examples 21-23

The following compounds were prepared according to the proceduredescribed previously:

Example 24N-(5-bromo-2-pyridinyl)-(2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonyl)amino)-4-aminophenylcarboxamide

A solution ofN-(5-bromo-2-pyridinyl)-(2-(4-[(2-t-butylsulfonyl)phenyl]phenylcarbonyl)amino)-4-nitrophenylcarboxamide(65 mg, 0.1 mmol, 1 equiv) in 10 mL of EtOAc was treated with SnCl₂.2H₂O(90 m g, 4 equiv) at reflux for 4 h. The volatile was evaporated and theresidue was redissolved in EtOAc, washed with saturated aqueous NaHCO₃and 1N NaOH. The organic layer was dried over MgSO₄, filtered andevaporated to giveN-(5-bromo-2-pyridinyl)-(2-(4-[(2-t-butylsulfonyl)phenyl]phenylcarbonyl)amino)-4-aminophenylcarboxamide, which was refluxed with 2 mL of TFA for 1 h. After removalof TFA by rotavap, the residue was purified by HPLC (C18 reversed phase)eluting with 0.5% TFA in H₂O/CH₃CN to giveN-(5-bromo-2-pyridinyl)-(2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonyl)amino)-4-aminophenylcarboxamide(47 mg, 84%). MS found for C₂₅H₂₁BrN₅O₄S (M+H)⁺: 566.

Example 25N-(5-chloro-2-pyridinyl)-(2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonyl)amino)-4-aminophenylcarboxamide

This compound was prepared according to the procedure described inexample 50. MS found for C₂₅H₂₁ClN₅O₄S (M+H)⁺: 522.

Example 26N-(5-bromo-2-pyridinyl)-(2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonyl)amino)-4-methylsulfonylaminophenylcarboxamide

A solution ofN-(5-bromo-2-pyridinyl)-(2-(4-[(2-t-butylsulfonyl)phenyl]phenylcarbonyl)amino)-4-aminophenylcarboxamide (62 mg, 0.1 mmol, 1 equiv) in 3 mL of CH₂Cl₂ was treatedwith MsCl (23 mg, 2 equiv) and TEA (0.5 mL) at rt for 4 h. The mixturewas washed with water and dried over MgSO₄, filtered and evaporated. Theresidue was refluxed with 2 mL of TFA for 1 h. After removal of TFA byrotavap, the residue was purified by HPLC (C18 reversed phase) elutingwith 0.5% TFA in H₂O/CH₃CN to giveN-(5-bromo-2-pyridinyl)-(2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonyl)amino)-4-methylsulfonylaminophenylcarboxamide(33 mg, 52%). MS found for C₂₆H₂₃BrN₅O₆S2 (M+H)⁺: 644.

Example 27N-(5-chloro-2-pyridinyl)-(2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonyl)amino)-4-methylsulfonylaminophenylcarboxamide

This compound was prepared according to the procedure described inexample 53. MS found for C₂₆H₂₃ClN₅O₆S₂ (M+H)⁺: 600.

Example 28N-(5-bromo-2-pyridinyl)-(2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonyl)amino)-5-aminophenylcarboxamide

This compound was prepared according to the procedure described inexample 50. MS found for C₂₅H₂₁BrN₅O₄S (M+H)⁺: 566.

Example 29N-(5-chloro-2-pyridinyl)-(2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonyl)amino)-5-aminophenylcarboxamide

This compound was prepared according to the procedure described inexample 50. MS found for C₂₅H₂₁ClN₅O₄S (M+H)⁺: 522.

Example 30N-(5-bromo-2-pyridinyl)-(2-(4-amidinophenylcarbonyl)amino)-phenylcarboxamide

Step 1: A mixture of N-(5-bromo-2-pyridinyl)-(2-amino)phenylcarboxamide(292 mg, 1 mmol, 1.0 equiv), 4-cyano benzoyl chloride (165 mg, 1 equiv),pyridine (3 mL) in 10 mL of dichloromethane was stirred at rt overnight,washed with H₂O. The organic layer was dried over MgSO₄, filtered,evaporated to giveN-(5-bromo-2-pyridinyl)-(2-(4-cyanophenylcarbonyl)amino)-phenylcarboxamide(349 mg, 70%). MS found for C₂₀H₁₄BrN₄O₂ (M+H)⁺: 421.

Step 2: A stream of HCl(g) was bubbled through a 0° C. solution ofN-(5-bromo-2-pyridinyl)-(2-(4-cyanophenylcarbonyl)amino)-phenylcarboxamide(49 mg, 0.1 mmol) in 5 mL of methanol until saturation. The mixture wasstirred at rt overnight and evaporated. The resulting residue wastreated with ammonium acetate (40 mg) in 10 ml methanol at refluxtemperature for 2 h. The solvent was removed at reduced pressure and thecrude benzamidine was purified by HPLC (C18 reversed phase) eluting with0.5% TFA in H₂O/CH₃CN to giveN-(5-bromo-2-pyridinyl)-(2-(4-amidinophenylcarbonyl)amino)-phenylcarboxamide(31 mg, 70%). MS found for C₂₀H₁₇BrN₅O₂(M+H)⁺: 438.

Examples 31-60

The following compounds were prepared according to the proceduredescribed previously

Example 61N-(5-bromo-2-pyridinyl)-(2-(4-(2-imidazolinyl)phenylcarbonyl)amino)-phenylcarboxamide

A stream of HCl(g) was bubbled through a 0° C. solution ofN-(5-bromo-2-pyridinyl)-(2-(4-cyanophenylcarbonyl)amino)-phenylcarboxamide(49 mg, 0.1 mmol) in 5 mL of methanol until saturation. The mixture wasstirred at rt overnight and evaporated. The resulting residue wastreated with ethylene diamine (40 mg) in 10 ml methanol at refluxtemperature for 2 h. The solvent was removed at reduced pressure and thecrude benzamidine was purified by HPLC (C18 reversed phase) eluting with0.5% TFA in H₂O/CH₃CN to giveN-(5-bromo-2-pyridinyl)-(2-(4-(2-imidazolinyl)phenylcarbonyl)amino)-phenylcarboxamide(41 mg, 89%). MS found for C₂₂H₁₉BrN₅O₂(M+H)⁺: 464.

Examples 62-70

The following compounds were prepared according to the procedurepreviously described

Example 71N-(5-bromo-2-pyridinyl)-(2-(4-(5-tetrazolyl)phenylcarbonyl)amino)-phenylcarboxamide

A mixture ofN-(5-bromo-2-pyridinyl)-(2-(4-cyanophenylcarbonyl)amino)-phenylcarboxamide(49 mg, 0.1 mmol) and sodium azide (67 mg, 10 equiv) in 5 mL of DMF washeated at 100° C. for 24 h. The reaction mixture was diluted with EtOAc,washed with water, dried, filtered and evaporated. The residue waspurified by HPLC (C18 reversed phase) eluting with 0.5% TFA in H₂O/CH₃CNto giveN-(5-bromo-2-pyridinyl)-(2-(4-(5-tetrazolyl)phenylcarbonyl)amino)-phenylcarboxamide(33 mg, 65%). MS found for C₂₀H₁₅BrN₇O₂(M+H)⁺: 464.

Example 72 and Example 73N-(5-bromo-2-pyridinyl)-(2-(4[-[1,1-doxo(1,4-thiazaperhydroin-4-yl))iminimethy]phenylcarbonyl)amino)-phenylcarboxamideandN-(5-bromo-2-pyridinyl)-(2-(4-[1-oxo(1,4-thiazaperhydroin-4-yl))iminimethy]phenylcarbonyl)amino)-phenylcarboxamide

A mixture ofN-(5-bromo-2-pyridinyl)-(2-(4-(1,4-thiazaperhydroin-4-yl)iminimethy]phenylcarbonyl)amino)-phenylcarboxamide(48 mg, 0.1 mmol) and 3 mL of 30% hydrogen doxide was stirred at rt for12 h. The reaction was quenched with solid Na₂S₂O₃. Purification by HPLC(C18 reversed phase) eluting with 0.5% TFA in H₂O/CH₃CN gaveN-(5-bromo-2-pyridinyl)-(2-(4[-[1,1-doxo(1,4-thiazaperhydroin-4-yl))iminimethy]phenylcarbonyl)amino)-phenylcarboxamide(15 mg, 31%), MS found for C₂₄H₂₃ClN₅O₄S (M+H)⁺: 512 andN-(5-bromo-2-pyridinyl)-(2-(4-[1-oxo(1,4-thiazaperhydroin-4-yl))iminimethy]phenylcarbonyl)amino)-phenylcarboxamide(20 mg, 41%). MS found for C₂₄H₂₃ClN₅O₃S (M+H)⁺: 496.

Examples 74-79

The following compounds were prepared according to the procedurepreviously described

Example 80N-(5-bromo-2-pyridinyl)-(2-4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)-4,5-difluorophenylcarboxamide

This compound was prepared according to the procedure previouslydescribed. MS found for C₂₅H₁₈BrF₂N₄O₄S (M+H)⁺: 587.

Example 81

Step 1: To a solution of 2-amino-5-chloropyridine (328 mg, 2.55 mmol) intetrahydrofuran (5 ml) was 0.5M potassium bis(trimethylsilyl)amide intoluene (10 ml, 5.05 mmol) dropwise at −78° C. After stirred foradditional 0.5 hr at −78° C., the mixture was added 5-chloroisatoicanhydride (0.5 g, 2.55 mmol) at −78° C. The mixture was warmed up to r.tgradually and stirred overnight. After quenched by saturated ammoniumchloride solution, the mixture was extracted by ethyl acetate. Theorganic layer was dried over magnesium sulfate and concentrated to give(2-amino-5-chlorophenyl)-N-(5-chloro(2-pyridyl))carboxamide (0.71 g.100%). MS found for C₁₂H₉Cl₂N₃₀ M⁺=282, (M+2)⁺=284.

Step 2: To a solution of the compound of(2-amino-5-chlorophenyl)-N-(5-chloro(2-pyridyl))carboxamide (0.71 g,2.52 mmol) in dichloromethane (10 ml) was added 3-cyanobenzoly chloride(417 mg, 2.52 mmol) and pyridine (0.611 ml, 7.55 mmol). The mixture wasstirred at r.t. overnight. The precipitate was filtered and washed withdichloromethane to giveN-{4-chloro-2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}(4-cyanophenyl)carboxamideas a solid (683 mg, 66%). MS found for C₂₀H12Cl2N4O2 M⁺=411, (M+2)⁺=413.

Step 3: To a solution of the compound ofN-{4-chloro-2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}(4-cyanophenyl)carboxamide(683 mg, 1.66 mmol) in anhydrous pyridine (10 ml) and triethyl amine (1ml) was saturated with hydrogen sulfide gas at 0° C. The mixture wasstirred at r.t. overnight. After the evaporated the solvent, the residuewas dissolved in anhydrous acetone (5 ml) and iodomethane (1 ml, 16.6mmol) was added. The mixture was stirred under reflux condition for 2hrs. After the evaporation of solvent, the residue was dissolved inanhydrous methanol (5 ml) and added a solution ofN-methylethylenediamine (0.732 ml, 8.3 mmol) and acetic acid (1.5 ml) inanhydrous methanol (5 ml). The mixture was stirred under refluxcondition for 2 hrs. After the evaporation of solvent, the crude residuewas purified by RP-HPLC to giveN-{4-chloro-2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}[4-(1-methyl(2-imidazolin-2-yl))phenyl]carboxamideas a white powder. MS found for C23H19Cl2N5O2 M⁺=468 (M+2)⁺=470.

Examples 82-106

The following compounds were prepared according to the procedurepreviously described

Example 107

Step 1: To a solution of 5-methyl-2-nitrobenzoic acid (1 g, 5.52 mmol)in dichloromethane (5 ml) was added oxalyl chloride (0.964 ml, 11.04mmol) and a few drops of dimethylformamide. The mixture was stirred atr.t. for 2 hrs. After the evaporation of the solvent, the residue wasdissolved in dichloromethane (5 ml). 2-amino-5-chloropyridine (852 mg,6.62 mmol) and pyridine (1.34 ml, 16.56 mmol) were added to thesolution. The mixture was stirred at r.t. overnight. After theevaporation of the solvent, the crude residue was purified by silica gelcolumn chromatography using solvent system 25% ethyl acetate in hexaneas eluent to giveN-(5-chloro(2-pyridyl))(5-methyl-2-nitrophenyl)carboxamide as a solid(1.48 g, 92%). MS found for C13H10ClN3O3 M⁺=291, (M+2)⁺=293.

Step 2: To a solution of the compound ofN-(5-chloro(2-pyridyl))(5-methyl-2-nitrophenyl)carboxamide (1.48 g, 5.1mmol) in methanol (10 ml) was added 5% Pt/C (1.48 g, 0.19 mmol). Themixture was applied hydrogen balloon at r.t. for 2 hrs. After thefiltration by Celite, the filtrate was concentrated to give(2-aminophenyl)-N-(2-pyridyl)carboxamide, C, chloride, N (1.36 g, 100%).MS found for C13H12ClN3O M⁺=262, (M+2)⁺=264.

Step 3: To a solution of the compound of(2-aminophenyl)-N-(2-pyridyl)carboxamide, C, chloride, N (1.36 g, 5.2mmol) in dichloromethane (10 ml) was added 3-cyanobenzoly chloride (860mg, 5.2 mmol) and pyridine (1.26 ml, 15.6 mmol). The mixture was stirredat r.t. overnight. After the evaporation of the solvent, the cruderesidue was purified by silica gel column chromatography using solventsystem 25% ethyl acetate in hexane as eluent to giveN-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-methylphenyl}(4-cyanophenyl)carboxamideas a solid (830 mg, 41%). MS found for C21H15ClN4O2 M⁺=390, (M+2)⁺=392.

Step 4: To a lotion of the compound ofN-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-methylphenyl}(4-cyanophenyl)carboxamide(830 mg, 2.1 mmol) in anhydrous methanol (5 ml) and ethyl acetate (10ml) was saturated with hydrogen chloride gas at 0° C. The mixture wasstirred at r.t. overnight. After the evaporated the solvent, the residuewas dissolved in anhydrous methanol (5 ml) and N-methylethylenediamine(0.926 ml, 10.5 mmol) was added. The mixture was stirred under refluxcondition for 2 hrs. After the evaporation of solvent, the crude residuewas purified by RP-HPLC to giveN-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-methylphenyl}[4-(1-methyl(2-imidazolin-2-yl))phenyl]carboxamideas a white powder. MS found for C24H22ClN5O2 M⁺=448, (M+2)±=450.

Examples 108-113

The following compounds were prepared according to the procedurepreviously described

Step 1: To a solution of 3,4,5-trimethoxy-2-nitrobenzoic acid (0.5 g,1.95 mmol) in dichloromethane (5 ml) was added oxalyl chloride (0.34 ml,3.9 mmol) and a few drops of dimethylformamide. The mixture was stirredat r.t. for 2 hrs. After the evaporation of the solvent, the residue wasdissolved in dichloromethane (5 ml). 2-amino-5-bromopyridine (0.81 g,4.7 mmol) and pyridine (0.94 ml, 11.7 mmol) were added to the solution.The mixture was stirred at r.t. overnight. After the evaporation of thesolvent, the crude residue was purified by silica gel columnchromatography using solvent system 25% ethyl acetate in hexane aseluent to giveN-(5-bromo(2-pyridyl))(3,4,5-trimethoxy-2-nitrophenyl)carboxamide as asolid (790 mg, 98%). MS found for C15H14BrN3O6 M⁺=412, (M+2)⁺=414.

Step 2: To a solution of the compound ofN-(5-bromo(2-pyridyl))(3,4,5-trimethoxy-2-nitrophenyl)carboxamide (790mg, 1.92 mmol) in ethyl acetate (5 ml) was added tin chloride (II)hydrate (1.73 g, 7.67 mmol). The mixture was stirred under refluxcondition for 2 hrs. After filtered by Celite, the filtrate was added 1Nsodium hydroxide solution and extracted with ethyl acetate. The organiclayer was dried over magnesium sulfate and concentrated to give(2-amino-3,4,5-trimethoxyphenyl)-N-(5-bromo(2-pyridyl))carboxamide (570mg, 77%). MS found for C15H16BrN3O4 M⁺=382, (M+2)⁺=384.

Step 3: To a solution of the compound of(2-amino-3,4,5-trimethoxyphenyl)-N-(5-bromo(2-pyridyl))carboxamide (570mg, 1.49 mmol) in dichloromethane (5 ml) was added 3-cyanobenzolychloride (247 mg, 1.49 mmol) and pyridine (0.362 ml, 4.48 mmol). Themixture was stirred at r.t. overnight. After the evaporation of thesolvent, the crude residue was purified by silica gel columnchromatography using solvent system 25% ethyl acetate in hexane aseluent to giveN-{6-[N-(5-bromo(2-pyridyl))carbamoyl]-2,3,4-trimethoxyphenyl}(4-cyanophenyl)carboxamideas a solid (680 mg, 69%). MS found for C23H19BrN4O5 M⁺=511, (M+2)⁺=513.

Step 4: To a solution of the compound ofN-{6-[N-(5-bromo(2-pyridyl))carbamoyl]-2,3,4-trimethoxyphenyl}(4-cyanophenyl)carboxamide(680 mg, 1.33 mmol) in anhydrous methanol (5 ml) and ethyl acetate (10ml) was saturated with hydrogen chloride gas at 0° C. The mixture wasstirred at r.t. overnight. After the evaporated the solvent, the residuewas dissolved in anhydrous methanol (5 ml) and N-methylethylenediamine(0.586 ml, 6.65 mmol) was added. The mixture was stirred under refluxcondition for 2 hrs. After the evaporation of solvent, the crude residuewas purified by RP-HPLC to giveN-{6-[N-(5-bromo(2-pyridyl))carbamoyl]-2,3,4-trimethoxyphenyl}[4-(1-methyl(2-imidazolin-2-yl))phenyl]carboxamideas a white powder (240 mg, 32%). MS found for C26H26BrN5O5 M⁺=568,(M+2)⁺=570.

Examples 115-118

The following compounds were prepared according to the procedurepreviously described

Step 1: To a solution of 4-{2-{[tert-butyl)amino}sulfonyl}phenyl}benzoicacid (167 mg, 0.5 mmol) in dichloromethane (5 ml) was added oxalylchloride (0.09 ml, 1 mmol) and a few drops of dimethylformamide. Themixture was stirred at r.t. for 2 hrs. After the evaporation of thesolvent, the residue was dissolved in dichloromethane (5 ml). Thecompound of (2-amino-5-chlorophenyl)-N-(5-chloro(2-pyridyl))carboxamide(0.17 g, 0.6 mmol) and pyridine (0.122 ml, 1.5 mmol) were added to thesolution. The mixture was stirred at r.t. overnight. The solvent wasevaporated to give(2-{[4-(2-{[tert-butyl)amino]sulfonyl}phenyl)phenyl]-carbonylamino}-5-chlorophenyl)-N-(5-chloro(2-pyridyl))carboxamide.MS found for C29H26Cl2N4O4S M⁺=597, (M+2)⁺=599.

Step 2: The mixture of the compound of(2-{[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]carbonylamino}-5-chlorophenyl)-N-(5-chloro(2-pyridyl))carboxamideexample 12 (0.5 mmol) in trifluoroacetic acid (5 ml) was stirred at r.t.for 5 hrs. After the evaporation of solvent, the crude residue waspurified by RP-HPLC to giveN-(5-chloro(2-pyridyl))(5-chloro-2-{[4-(2-sulfamoylphenyl)-phenyl]carbonylamino}phenyl)-carboxamideas a white powder (68 mg, 25%). MS found for C25H18Cl2N4O4S M⁺=541,(M+2)±=543.

Example 1202-[4-(N-{2-[N-(5-chloro-2-pyridyl)carbamoyl]phenyl}carbamoyl)phenyl]-benzenecarboxamidine

A stream of H₂S (g) was bubbled through a 0° C. solution ofN-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}[4-(2-cyanophenyl)phenyl]carboxamide(100 mg, 0.22 mmol, 1.0 equiv.) in 9 mL pyridine and 1 mL NEt₃ untilsaturation. The mixture was stirred at rt for 1 day and evaporated. Theresulting residue was treated with MeI (94 mg, 0.663 mmol, 3.0 equiv.)in 10 mL acetone at reflux temperature for 1 hr and concentrated todryness. The resulting residue was treated with a mixture of NH₄OAc (340mg, 4.42 mmol, 20 equiv.) in 0.5 mL acetic acid and 2 mL methanol at 50°C. for 2 days. The solvent was removed at reduced pressure and the crudebenzamidine was purified by HPLC (C18 reversed phase) eluting with 0.1%TFA in H₂O/CH₃CN to give2-[4-(N-{2-[N-(5-chloro-2-pyridyl)carbamoyl]phenyl}carbamoyl)phenyl]benzenecarboxamidine(15 mg, 15%). MS found for C₂₆H₂₀ClN₅O₂ (M+H)⁺: 470.

Example 121(4-{2-[(dimethylamino)iminomethyl]phenyl}phenyl)-N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}carboxamide

This compound was prepared according to the procedure previouslydescribed. MS found for C₂₈H₂₄ClN₅O₂ (M+H)⁺: 498.

Example 122N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}{4-[2-((hydroxyamino)iminomethyl)-phenyl]phenyl}carboxamide

A mixture ofN-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}[4-(2-cyanophenyl)phenyl]carboxamide(14 mg, 0.03 mmol, 1.0 equiv.), hydroxyamine hydrochloride (6.25 mg,0.09 mmol, 3.0 equiv.) and triethyl amine (0.03 mL, 0.3 mmol, 10.0equiv.) in ethanol (3 mL) was stirred at rt for 6 days, concentrated andHPLC (C18 reversed phase) eluting with 0.1% TFA in H₂O/CH₃CN to giveN-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}{4-[2-((hydroxyamino)iminomethyl)phenyl]phenyl}carboxamide(4 mg, 27.5%). MS found for C₂₆H₂₀ClN₅O₃ (M+H)⁺: 486.

Example 1232-[4-(N-{2-[N-(5-chloro-2-pyridyl)carbamoyl]phenyl}carbamoyl)phenyl]benzamide

This compound was obtained as one of the side product in Example 122. MSfound for C₂₆H₁₉ClN₄O₃ (M+H)⁺: 471

Example 124{4-[2-(aminomethyl)phenyl]phenyl}-N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-phenyl}carboxamide

A mixture ofN-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}[4-(2-cyanophenyl)phenyl]carboxamide(200 mg, 0.442 mmol, 1.0 equiv.), cobalt chloride (86 mg, 0.664 mmol,1.5 equiv.) and sodium borohydride (50 mg, 1.33 mmol, 3.0 equiv.) in DMF(15 mL) was stirred at 0° C. to rt for 3 days. The reaction was quenchedwith ice cubes, diluted with DCM (100 mL) and filtered through celite.The filtrate was washed with saturated aqueous NaHCO₃. The organic layerwas dried over MgSO₄, filtered, evaporated and HPLC (C18 reversed phase)eluting with 0.1% TFA in H₂O/CH₃CN gave{4-[2-(aminomethyl)phenyl]phenyl}-N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}carboxamide(87 mg, 43%). MS found for C₂₆H₂₁ClN₄O₂ (M+H)⁺: 457.

Example 125[4-(aminomethyl)phenyl]-N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}carboxamide

A mixture ofN-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}(4-cyanophenyl)carboxamide(1 g, 2.6 mmol, 1.0 equiv.), cobalt chloride (0.5 g, 3.85 mmol, 1.5equiv.) and sodium borohydride (0.295 g, 7.8 mmol, 3.0 equiv.) in DMF(20 mL) was stirred at 0° C. to rt for 2.5 hr. The reaction was quenchedwith ice cubes, diluted with ethyl acetate (100 mL) and filtered throughcelite. The filtrate was washed with saturated aqueous NaHCO₃. Theorganic layer was dried over MgSO₄, filtered, evaporated and HPLC (C18reversed phase) eluting with 0.1% TFA in H₂O/CH₃CN gave[4-(aminomethyl)phenyl]-N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}carboxamide(320 mg, 30%). MS found for C₂₀H₁₇ClN₄O₂ (M+H)⁺: 381.

Example 126N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}{4-[(2-imidazolin-2-ylamino)methyl]-phenyl}carboxamide

A mixture of[4-(aminomethyl)phenyl]-N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}carboxamide(80 mg, 0.21 mmol), 2-methylthio-2-imidazoline hydriodide (77 mg, 0.315mmol, 1.5 equiv.) and triethyl amine (0.5 mL) in 1 mL DMF was stirred atroom temperature overnight, concentrated to dryness and HPLC (C18reversed phase) eluting with 0.1% TFA in H₂O/CH₃CN gaveN-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}{4-[(2-imidazolin-2-ylamino)methyl]phenyl}carboxamide(13.5 mg, 15%). MS found for C₂₃H₂₁ClN₆O₂ (M+H)⁺: 449

Example 127N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}(4-{[(1-methyl(2-imidazolin-2-yl))amino]methyl}phenyl)carboxamide

Step 1: To the boiling solution of 2-methylthio-2-imidazoline hydriodide(1 g, 8.4 mmol) in methanol (10 mL) was added MeI (0.78 mL, 12.6 mmol,1.5 equiv.) dropwise. The reaction mixture was stirred at refluxtemperature for 1 hr, concentrated and crystallized with ether to give1-methyl-2-methylthio-2-imidazoline (1.1 g, 100%).

MS found for C₅H₁₀N₂S (M+H)⁺: 131.

Step 2: A mixture of[4-(aminomethyl)phenyl]-N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}carboxamide(74 mg, 0.195 mmol), 1-methyl-2-methylthio-2-imidazoline (25 mg, 0.195mmol), NEt3 (2 mL) and pyridine (5 mL) was stirred at 80° C. overnight,concentrated and HPLC (C18 reversed phase) eluting with 0.1% TFA inH2O/CH3CN gaveN-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}(4-{[1-methyl(2-imidazolin-2-yl))amino]methyl}phenyl)carboxamide(52 mg, 65%). MS found for C₂₄H₂₃ClN₆O₂ (M+H)⁺: 463.

Example 128N-(5-bromo-2-pyridinyl)-(2-4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)-5-fluorophenylcarboxamide

Step 1: A solution of 5-fluoro-2-nitrobenzoic acid (10.0 g, 54 mmol, 1.0equiv), 2-amino-5-bromopyridine (12.2 g, 1.3 equiv), in 80 mL ofpyridine was treated with phosphorous oxychloride (25.3 g, 3.0 equiv)for 30 min. The volatile was evaporated and the residue was redissolvedinto EtOAc, washed with 1N HCl, saturated aqueous NaHCO₃ and saturatedaqueous NaCl. The organic layer was dried over Na₂SO₄, filtered, andevaporated. The volatile was evaporated, and the product was trituratedwith diethyl ether to giveN-(5-bromo-2-pyridinyl)-(2-nitro)-5-fluorophenylcarboxamide (12.5 g,68%). MS found for C₁₂H₇BrFN₃O₃ (M+H)⁺: 340, 342.

Step 2: A solution ofN-(5-bromo-2-pyridinyl)-(2-nitro)-5-fluorophenylcarboxamide (2.0 g, 5.88mmol, 1.0 equiv) in 30 mL of EtOAc was treated with SnCl₂.2H₂O (5.90 g,4 equiv) at reflux for 4 h. The volatile was evaporated and the residuewas redissolved in EtOAc, washed with saturated aqueous NaHCO₃ and 1NNaOH. The organic layer was dried over MgSO₄, filtered and evaporated toN-(5-bromo-2-pyridinyl)-(2-amino)-5-fluorophenylcarboxamide (1.79 g,98%). MS found for C₁₂H₉BrFN₃O (M+H)⁺: 310, 312.

Step 3: A mixture ofN-(5-bromo-2-pyridinyl)-(2-amino)-5-fluorophenylcarboxamide (0.310 g, 1mmol, 1.0 equiv), 4-[(2-t-butylaminosulfonyl)phenyl]benzoyl chloride(0.430 g, 1.3 equiv), pyridine (2 mL) in 10 mL of dichloromethane wasstirred at rt overnight The volatile was evaporated and the residue wasredissolved into EtOAc, washed with 1N HCl, saturated aqueous NaHCO₃ andsaturated aqueous NaCl. The organic layer was dried over Na₂SO₄,filtered, and evaporated. The intermediate was reacted into 5 mL oftrifluoroacetic acid at rt overnight. TFA was then evaporated and theproduct was triturated with diethyl ether, and then with chloroform togiveN-(5-bromo-2-pyridinyl)-(2-4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)-5-fluorophenylcarboxamide(120 mg, 21%). MS found for C₂₅H₁₈BrFN₄O₄S (M+H)⁺: 569, 571.

Example 129

This compound was prepared according to the procedure described inexample 2 with the exception of using zinc in acetic acid to reducenitro-intermediate in step 2. The final product was purified by HPLC(C18 reversed phase) eluting with 0.5% TFA in H₂O/CH₃CN. MS found forC₂₅H₁₈ClFN₄O₄S (M+H)⁺: 525, 527.

Example 130

This compound was prepared according to the procedure described inexample 2 with the exception of using 5-acetamido-2-nitrobenzoic acid asthe starting material in step 1. The final product was purified by HPLC(C18 reversed phase) eluting with 0.5% TFA in H₂O/CH₃CN MS found forC₂₇H₂₂BrN₅O₅S (M+H)⁺: 608, 610.

Example 131

This compound is prepared according to the procedure described inexample 2 with the exception of the following step 1b performed on thenitro-intermediate from step 1. The final product was purified by HPLC(C18 reversed phase) eluting with 0.5% TFA in H₂O/CH₃CN MS found forC₃₀H₂₉BrN₆O₄S (M+H)⁺: 649, 651.

Step 1b: A mixture ofN-(5-bromo-2-pyridinyl)-(2-nitro)-5-fluorophenylcarboxamide (0.68 g, 2mmol, 1.0 equiv), N-methylpiperazine (0.60 g, 3 equiv), and Cs₂CO₃ (1.30g, 2 equiv) in 5 mL of dimethylformamide was stirred at 90° C.overnight. Ethyl acetate was added and washed with H₂O. The organiclayer was dried over Na₂SO₄, filtered, evaporated, purified via flashchromatography on silica gel to giveN-(5-bromo-2-pyridinyl)-(2-nitro)-5-(4-N-methylpiperazine)phenylcarboxamide(0.54 g, 65%). MS found for C₁₇H₁₈BrN₅O₃ (M+H)⁺: 419, 421.

Example 132

This compound was prepared according to the procedure described inexample 5. The final product was purified by HPLC (C18 reversed phase)eluting with 0.5% TFA in H₂O/CH₃CN MS found for C₂₈H₂₁ClN₆O₄S (M+H)⁺:573, 575.

Example 133N-(5-bromo-2-pyridinyl)-(2-4-[(2-aminosulfonyl)phenyl]phenylaminocarbonylamino)-5-fluorophenylcarboxamide

Step 3: A mixture of 4-[(2-t-butylaminosulfonyl)-phenyl]phenylamine(0.180 g, 1.2 equiv), N,N′-disuccinimidyl carbonate (0.154 g, 1.2equiv), 4-methylmorpholine (0.5 mL) in 10 mL of acetonitrile was stirredat rt for 30 min.N-(5-bromo-2-pyridinyl)-(2-amino)-5-fluorophenylcarboxamide (0.155 g,0.5 mmol, 1.0 equiv) was added and the solution was stirred at rt for 3hrs. The volatile was evaporated and the residue was redissolved intoEtOAc, washed with 1N HCl, saturated aqueous NaHCO₃ and saturatedaqueous NaCl. The organic layer was dried over Na₂SO₄, filtered, andevaporated. The intermediate was reacted into 5 mL of trifluoroaceticacid at rt overnight. TFA was then evaporated and the product waspurified by HPLC (C18 reversed phase) eluting with 0.5% TFA in H₂O/CH₃CNto giveN-(5-bromo-2-pyridinyl)-(2-4-[(2-aminosulfonyl)-phenyl]phenylaminocarbonylamino)-5-fluorophenylcarboxamide(0.053 g, 18%). MS found for C₂₅H₁₉BrFN₅O₄S (M+H)⁺: 584, 586.

Examples 134-135N-(5-bromo-2-pyridinyl)-(2-(4-amidinophenylcarbonyl)amino)5-fluorophenylcarboxamide

Step 1: A mixture ofN-(5-bromo-2-pyridinyl)-(2-amino)5-fluorophenylcarboxamide (1.24 g, 4mmol, 1.0 equiv), 4-cyano benzoyl chloride (0.792 g, equiv), andpyridine (3 mL) in 15 mL of dichloromethane was stirred at rt overnight.The volatile was evaporated and the residue was redissolved into EtOAc,washed with 1N HCl, saturated aqueous NaHCO₃ and saturated aqueous NaCl.The organic layer was dried over Na₂SO₄, filtered, and evaporated togiveN-(5-bromo-2-pyridinyl)-(2-(4-cyanophenylcarbonyl)amino)5-fluorophenylcarboxamide(1.14 g, 65%). MS found for C₂₀H₁₂BrFN₄O₂ (M+H)⁺: 439, 441.

Step 2: A mixture ofN-(5-bromo-2-pyridinyl)-(2-(4-cyanophenylcarbonyl)amino)5-fluorophenylcarboxamide(1.12 g, 2.56 mmol, 1.0 equiv), hydroxylamine-HCl (0.213 g, 1.2 equiv),and triethylamine (1 mL) in 15 mL of ethyl alcohol was stirred at 50° C.overnight. The volatile was evaporated and the residue was redissolvedinto EtOAc, washed with 1N HCl, saturated aqueous NaHCO₃ and saturatedaqueous NaCl. The organic layer was dried over Na₂SO₄, filtered, andevaporated to giveN-(5-bromo-2-pyridinyl)-(2-(4-hydroxyamidinophenylcarbonyl)amino)5-fluorophenylcarboxamide(compound Example 194) (0.84 g, 70%). One third of this material waspurified by HPLC (C18 reversed phase) eluting with 0.5% TFA in H₂O/CH₃CNto yield 0.20 grams (71%). MS found for C₂₀H₁₅BrFN₅O₃ (M+H)⁺: 472, 474.

Step 3: A mixture ofN-(5-bromo-2-pyridinyl)-(2-(4-hydroxyamidinophenylcarbonyl)amino)5-fluorophenylcarboxamide(0.56 g, 1.19 mmol, 1.0 equiv) and zinc dust (0.39 g, 5.0 equiv), in 10mL of acetic acid was stirred at rt for 45 min. The volatile wasfiltered and evaporated. The residue was purified by HPLC (C18 reversedphase) eluting with 0.5% TFA in H₂O/CH₃CN giveN-(5-bromo-2-pyridinyl)-(2-(4-amidinophenylcarbonyl)amino)5-fluorophenyl-carboxamide(compound Example 195) (0.24 g, 44%).

MS found for C₂₀H₁₅BrFN₅O₂ (M+H)⁺: 456, 458.

Example 136N-(5-bromo-2-pyridinyl)-(2-(4-(1-methyl-2-imadazolin-2-yl)phenylcarbonyl)amino)5-fluorophenylcarboxamide

Step 1: A stream of HCl(g) was bubbled through a 0° C. solution ofN-(5-bromo-2-pyridinyl)-(2-(4-cyanophenylcarbonyl)amino)5-fluorophenylcarboxamide(1.0 g, 2.3 mmol) in 30 mL of methanol until saturation. The mixture wasstirred at rt overnight and evaporated. One-fifth of the resultingresidue was treated with (2-aminoethyl)methylamine (0.10 g) in 10 mlmethanol at rt overnight. The solvent was removed at reduced pressureand the crude product was purified by HPLC (C18 reversed phase) elutingwith 0.5% TFA in H₂O/CH₃CN to giveN-(5-bromo-2-pyridinyl)-(2-(4-(1-methyl-2-imadazolin-2-yl)phenylcarbonyl)amino)5-fluorophenylcarboxamide(0.082 g, 37%). MS found for C₂₃H₁₉BrFN₅O₂(M+H)⁺: 496, 498.

Examples 137-198

The following compounds were prepared generally according to theprocedure described in Example 196.

Example 199N-{2-[N-(5-bromo(2-pyridyl))carbamoyl]-4,5-dimethoxyphenyl}(4-cyanophenyl)carboxamide

To a solution of 4,5-dimethoxy-2-nitrobenzoic acid (2.2 gm, 10 mmol) and2-amino-5-bromopyridine (2.4 gm, 14 mmol) in anhydrous pyridine (50 mL)at 0° C. was added POCl₃ (1.9 mL, 20 mmol). After stirring at roomtemperature for 30 min, the reaction was complete. The mixture wasconcentrated and diluted with EtOAc (200 mL). The organic solution waswashed with brine, dried and evaporated to give intermediate compound 1(3.0 gm, 80%). MS found for C₁₋₄H₁₂BrN₃O₅ (M+H)⁺: 382.00, 383.95.

A mixture of intermediate compound 1 (320 mg, 0.83 mmol) and SnCl₂.2H₂O(900 mg, 4.0 mmol) in EtOAc (10 mL) was refluxed for 1 hour. Reductioncompleted. The solid was filtered through a celite bed. The filtrate wasdiluted with EtOAc (50 mL), and the red solution was washed with 1N aq.NaOH solution (×3) and brine, dried and evaporated to give intermediatecompound 2 (230 mg, 78%). MS found for C₁₄H₁₄BrN₃O₃ (M+H)⁺: 352.00,354.05.

To a solution of intermediate compound 2 (200 mg, 0.57 mmol) in amixture of pyridine (3 mL) and DCM (10 mL) was added 4-cyanobenzoylchloride (140 mg, 0.85 mmol). Precipitate formed immediately and thereaction was complete. The solid was collected by filtration and washedwith DCM. After drying in vacco, the titled compound was obtained as ayellow solid in 70% yield (190 mg). MS found for C₂₂H₁₇BrN₄O₄ (M+H)⁺:481.00, 483.00.

Example 200(4,5-dimethoxy-2-{[4-(1-methyl(2-imidazolin-2-yl))phenyl]carbonylamino}phenyl)-N-(5-bromo(2-pyridyl))carboxamide

To a solution of compound obtained in Example 259 (100 mg, 0.20 mmol) in10% Et₃N/pyridine (10 mL) at 0° C. was bubbled dry H₂S gas tosaturation. The mixture was stirred at ambient temperatures overnight,and the conversion was complete. The solvent was removed to dryness, andthe residue was suspended in anhydrous acetone (10 mL), followed byaddition of MeI (1 mL). The reaction mixture was refluxed for 1 hour.The solvent was removed by rotary evaporation. To the residue was addedanhydrous MeOH (10 mL) and N-methylethylenediamine (1 mL). The resultingmixture was refluxed for 1 hour, concentrated and subjected to RP-HPLCpurification to give the title compound. MS found for C₂₅H₂₄BrN₅O₄(M+H)⁺: 538.1, 540.1.

Example 2014-(N-{2-[N-(5-bromo(2-pyridyl))carbamoyl]-4,5-dimethoxyphenyl}carbamoyl)-benzenecarboxamidine

The title compound was obtained according to the procedure previouslydescribed. MS found for C₂₂H₂₀BrN₅O₄ (M+H)⁺: 498.1, 500.0.

Example 202N-(5-chloro(2-pyridyl)){2-[(4-cyanophenyl)carbonylamino]-5-methoxyphenyl}-carboxamide

The title compound was obtained according to the procedure previouslydescribed. MS found for C₂₁H₁₅ClN₄O₃ (M+H)⁺: 407.0.

Example 203N-(5-chloro(2-pyridyl))(5-methoxy-2-[{4-(1-methyl(2-imidazolin-2-yl))phenyl]-carbonylamino}phenyl)carboxamide

To the suspension of the compound Example 262 (100 mg) in a mixture ofanhydrous MeOH (5 mL) and EtOAc (5 mL) at 0° C. was bubbled anhydrousHCl gas to saturation. The mixture was stirred at ambient temperaturesovernight. The conversion completed. The solvent was evaporated todryness. The residue was dissolved in anhydrous MeOH (10 mL), followedby addition of N-methylethylenediamine (1 mL). The resulting mixture wasrefluxed for 1 hour, concentrated and subjected to RP-HPLC purificationto give the title compound 263. MS found for C₂₄H₂₂ClN₅O₃ (M+H)⁺: 464.

Example 2044-(N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-methoxyphenyl}carbamoyl)benzene-carboxamidine

The title compound was obtained according to the procedure previouslydescribed. MS found for C₂₁H₁₈ClN₅O₃ (M+H)⁺: 424.

Example 205N-(5-chloro(2-pyridyl))[2-({4-[imino(methylamino)methyl]phenyl}carbonylamino)-5-methoxyphenyl]carboxamide

The title compound was obtained according to the procedure previouslydescribed. MS found for C₂₂H₂₀ClN₅O₃ (M+H)⁺: 438.

Example 206[2-({4-[(dimethylamino)iminomethyl]phenyl}carbonylamino)-5-methoxyphenyl]-N-(5-chloro(2-pyridyl))carboxamide

The title compound was obtained according to the procedure previouslydescribed. MS found for C₂₃H₂₂ClN₅O₃ (M+H)⁺: 452.

Example 207N-(5-chloro(2-pyridyl))(2-{[4-(iminopyrrolidinylmethyl)phenyl]carbonylamino}-5-methoxyphenyl)carboxamide

The title compound was obtained according to the procedure previouslydescribed. MS found for C₂₅H₂₄ClN₅O₃ (M+H)⁺: 478.

Example 208N-(5-chloro(2-pyridyl))(2-{[4-(iminopiperidylmethyl)phenyl]carbonylamino}-5-methoxyphenyl)carboxamide

The title compound was obtained according to the procedure previouslydescribed. MS found for C₂₆H₂₆ClN₅O₃ (M+H)⁺: 492.

Example 209N-(5-chloro(2-pyridyl))(2-{[4-(iminomorpholin-4-ylmethyl)phenyl]carbonylamin}-5-methoxyphenyl)carboxamide

The title compound was obtained according to the procedure previouslydescribed. MS found for C₂₅H₂₄ClN₅O₄ (M+H)⁺: 494.1.

Example 210N-(5-chloro(2-pyridyl))(2-{[4-(imino-1,4-thiazaperhydroin-4-ylmethyl)phenyl]carbonylamino}-5-methoxyphenyl)carboxamide

The title compound was obtained according to the procedure previouslydescribed. MS found for C₂₅H₂₄ClN₅O₃S (M+H)⁺: 510.

Example 211

(2-{[4-(amino(hydroxyimino)methyl)phenyl]carbonylamino}-5-methoxyphenyl)-N-(5-chloro(2-pyridyl))carboxamide

To a suspension of compoundN-(5-chloro(2-pyridyl)){2-[(4-cyanophenyl)carbonylamino]-5-methoxyphenyl}carboxamide(150 mg) in EtOH (10 mL) was added hydroxyamine hydrochloride (80 mg)and Et₃N (200 μL). The mixture was stirred at 60° C. overnight and thereaction was complete. The solvent was evaporated and the crude materialwas purified by RP-HPLC to give the title compound. MS found forC₂₁H₁₈ClN₅O₄ (M+H)⁺: 440.1.

Example 212N-(5-bromo(2-pyridyl)){2-[(4-cyanophenyl)carbonylamino]-5-methoxyphenyl}carboxamide

The title compound was obtained according to the procedure previouslydescribed. MS found for C₂₁H₁₅BrN₄O₃ (M+H)⁺: 451.00, 453.00.

Example 213N-(5-bromo(2-pyridyl))(5-methoxy-2-{[4-(1-methyl(2-imidazolin-2-yl))phenyl]carbonylamino}phenyl)carboxamide

The title compound was obtained according to the procedure previouslydescribed. MS found for C₂₄H₂₂BrN₅O₃ (M+H)⁺: 508, 510.

Example 2144-(N-{2-[N-(5-bromo(2-pyridyl))carbamoyl]-4-methoxyphenyl}carbamoyl)benzenecarboxamidine

The title compound was obtained according to the procedure previouslydescribed. MS found for C₂₁H₁₈BrN₅O₃ (M+H)⁺: 468.05, 470.00.

Example 215 N-(5-bromo(2-pyridyl))[2-({4-[imino(methylamino)methyl]phenyl}carbonylamino)-5-methoxyphenyl]carboxamide

The title compound was obtained according to the procedure previouslydescribed. MS found for C₂₂H₂₀BrN₅O₃ (M+H)⁺: 482, 484.

Example 216[2-({4-[(dimethylamino)iminomethyl]phenyl}carbonylamino)-5-methoxyphenyl]-N-(5-bromo(2-pyridyl))carboxamide

The title compound was obtained according to the procedure previouslydescribed. MS found for C₂₃H₂₂BrN₅O₃ (M+H)⁺: 496.1, 498.1.

Example 217N-(5-chloro(2-pyridyl))(2-{[4-(iminopyrrolidinylmethyl)phenyl]carbonylamino}-5-methoxyphenyl)carboxamide

The title compound was obtained according to the procedure previouslydescribed. MS found for C₂₅H₂₄BrN₅O₃ (M+H)⁺: 522, 524.

Example 218N—(N-(5-bromo(2-pyridyl))(2-{[4-(iminopiperidylmethyl)phenyl]carbonylamino}-5-methoxyphenyl)carboxamide

The title compound was obtained according to the procedure previouslydescribed. MS found for C₂₆H₂₆BrN₅O₃ (M+H)⁺: 536.1, 538.1.

Example 219N-(5-bromo(2-pyridyl))(2-{[4-(iminomorpholin-4-ylmethyl)phenyl]carbonylamino}-5-methoxyphenyl)carboxamide

The title compound was obtained according to the procedure previouslydescribed. MS found for C₂₅H₂₄BrN₅O₄ (M+H)⁺: 538.1, 540.1.

Example 220N-(5-bromo(2-pyridyl))(2-{[4-(imino-1,4-thiazaperhydroin-4-ylmethyl)phenyl]carbonylamino}-5-methoxyphenyl)carboxamide

The title compound was obtained according to the procedure previouslydescribed. MS found for C₂₅H₂₄BrN₅O₃S (M+H)⁺: 554.1, 556.05.

Example 221(2-{[4-(amino(hydroxyimino)methyl)phenyl]carbonylamino}-5-methoxyphenyl)-N-(5-bromo(2-pyridyl))carboxamide

The title compound was obtained according to the procedure previouslydescribed. MS found for C₂₁H₁₈BrN₅O₄ (M+H)⁺: 484.1, 486.0.

Example 222N-(5-chloro(2-pyridyl)){6-[(4-cyanophenyl)carbonylamino]-3-hydroxyphenyl}carboxamide

To a suspension of compoundN-(5-chloro(2-pyridyl)){2-[(4-cyanophenyl)-carbonylamino]-5-methoxyphenyl}carboxamide(500 mg, 1.2 mmol) in DCM (100 mL) at −78° C. was added BBr₃ (2 mL). Themixture was stirred at ambient temperatures for 72 hours. The solid wascollected by filtration and was washed by DCM and water, dried undervacuum. The filtrate was concentrated and extracted with EtOAc. Theorganic extract was washed with brine, dried and evaporated. Theresulting solid was combined with the solid obtained from filtration togive the title compound. Total yield is 90% (430 mg). MS found forC₂₀H₁₃ClN₄O₃ (M+H)⁺: 393.0.

Example 223 ethyl2-{3-[N-(5-chloro(2-pyridyl))carbamoyl]-4-[(4-cyanophenyl)carbonylamino]-phenoxy}acetate

To a mixture of compoundN-(5-chloro(2-pyridyl)){6-[(4-cyanophenyl)-carbonylamino]-3-hydroxyphenyl}carboxamide(50 mg, 0.13 mmol) and Cs₂CO₃ (83 mg, 0.25 mmol) in DMF (1 mL) at roomtemperature was added ethyl bromoacetate (15 μL, 0.13 mmol). The mixturewas stirred for 1 hour before diluted with EtOAc (20 mL) and water (10mL). The organic layer was washed with brine dried and evaporated togive 70 mg of the crude compound, which was used without fartherpurification. MS found for C₂₄H₁₉ClN₄O₅ (M+H)⁺: 479.0.

Example 224 methyl2-[4-({4-[(dimethylamino)iminomethyl]phenyl}carbonylamino)-3-[N-(5-chloro(2-pyridyl))carbamoyl]phenoxy]acetate

The title compound was obtained according to the procedure previouslydescribed. MS found for C₂₅H₂₄ClN₅O₅ (M+H)⁺: 510.1.

Example 225(6-{[4-(amino(hydroxyimino)methyl)phenyl]carbonylamino}-3-hydroxyphenyl)-N-(5-chloro(2-pyridyl))carboxamide

The title compound was obtained according to the procedure previouslydescribed. MS found for C₂₀H₁₆ClN₅O₄ (M+Na)⁺: 448.0.

Example 2264-(N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-hydroxyphenyl}carbamoyl)-benzenecarboxamidine

The title compound was obtained according to the procedure previouslydescribed. MS found for C₂₀H₁₆ClN₅O₃ (M+H)⁺: 410.1.

Example 2274-(N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-hydroxyphenyl}carbamoyl)-benzenecarboxamidine

To a solution of Example 284 (10 mg) in MeOH (1 mL) was added 50 μL of1N aq. LiOH solution. The mixture was stirred for 1 hour and purified byRP-HPLC to give the title compound. MS found for C₂₄H₂₂ClN₅O₅ (M+H)⁺:496.

Example 228

The title compound was synthesized according to the procedure describedpreviously. MS found for C₂₄H₂₁ClFN₅O₃: (M+H)⁺: 482.1.

Example 229

The title compound was synthesized according to the procedure describedpreviously. MS found for C₂₁H₁₇ClFN₅O₃: (M+H)⁺: 442.1.

Example 230

The title compound was synthesized according to the procedure describedpreviously. MS found for C₂₂H₁₉ClFN₅O₃: (M+H)⁺: 456.1.

Example 231

The title compound was synthesized according to the procedure describedpreviously. MS found for C₂₃H₂₁ClFN₅O₃: (M+H)⁺: 470.1.

Example 232

The title compound was synthesized according to the procedure describedpreviously. MS found for C₂₄H₂₁ClFN₅O₃: (M+H)⁺: 482.1.

Example 233

The title compound was synthesized according to the procedure describedpreviously. MS found for C₂₅H₂₃ClFN₅O₃: (M+H)⁺: 496.1.

Example 234

The title compound was synthesized according to the procedure describedpreviously. MS found for C₂₆H₂₅ClFN₅O₃: (M+H)⁺: 510.2.

Example 235

The title compound was synthesized according to the procedure describedpreviously. MS found for C₂₅H₂₃ClFN₅O₄: (M+H)⁺: 512.2.

Example 236

The title compound was synthesized according to the procedure describedpreviously. MS found for C₂₅H₂₃ClFN₅O₃S: (M+H)⁺: 528.1.

Example 237

The title compound was synthesized according to the procedure describedpreviously. MS found for C₂₁H₁₇ClFN₅O₄: (M+H)⁺: 458.1.

Example 238

The title compound was synthesized according to the procedure describedpreviously. MS found for C₂₇H₂₆ClN₅O₅: (M+H)⁺: 536.1.

Example 239

The title compound was synthesized according to the procedure describedpreviously. MS found for C₂₅H₂₂ClN₅O₅: (M+H)⁺: 508.1.

Example 240

The title compound was synthesized according to the procedure describedpreviously. MS found for C₂₄H₂₂ClN₅O₅: (M+H)⁺: 496.1.

Example 241

The title compound was synthesized according to the procedure describedpreviously. MS found for C₂₂H₁₈ClN₅O₅: (M+H)⁺: 468.1.

Example 242

The title compound was synthesized according to the procedure describedpreviously. MS found for C₂₆H₂₆ClN₅O₅: (M+H)⁺: 524.2.

Example 243

The title compound was synthesized according to the procedure describedpreviously. MS found for C₂₇H₂₆ClN₅O₅: (M+H)⁺: 536.1.

Example 244

The title compound was synthesized according to the procedure describedpreviously. MS found for C₂₅H₂₂ClN₅O₅: (M+H)⁺: 508.1.

Example 245

The title compound was synthesized according to the procedure describedpreviously. MS found for C₂₈H₂₈ClN₅O₅: (M+H)⁺: 550.2.

Example 246

The title compound was synthesized according to the procedure describedpreviously. MS found for C₂₆H₂₄ClN₅O₅: (M+H)⁺: 522.1.

Example 247

The title compound was synthesized according to the procedure describedpreviously. MS found for C₂₉H₃₀ClN₅O₅: (M+H)⁺: 564.2.

Example 248

The title compound was synthesized according to the procedure describedpreviously. MS found for C₂₇H₂₆ClN₅O₅: (M+H)⁺: 536.1.

Example 249

The title compound was synthesized according to the procedure describedpreviously. MS found for C₂₇H₂₅ClFN₅O₅: (M+H)⁺: 554.2.

Example 250

The title compound was synthesized according to the procedure describedpreviously. MS found for C₂₅H₂₁ClFN₅O₅: (M+H)⁺: 526.1.

Example 251

The title compound was synthesized according to the procedure describedpreviously. MS found for C₂₄H₂₁ClFN₅O₅: (M+H)⁺: 514.1.

Example 252

The title compound was synthesized according to the procedure describedpreviously. MS found for C₂₂H₁₇ClFN₅O₅: (M+H)⁺: 486.

Example 253

The title compound was synthesized according to the procedure describedpreviously. MS found for C₂₆H₂₅ClFN₅O₅: (M+H)⁺: 542.1.

Example 254

The title compound was synthesized according to the procedure describedpreviously. MS found for C₂₄H₂₁ClFN₅O₅: (M+H)⁺: 514.1.

Example 255

The title compound was synthesized according to the procedure describedpreviously. MS found for C₂₇H₂₅ClFN₅O₅: (M+H)⁺: 554.1.

Example 256

The title compound was synthesized according to the procedure describedpreviously. MS found for C₂₅H₂₁ClFN₅O₅: (M+H)⁺: 526.1.

Example 257

The title compound was synthesized according to the procedure describedpreviously. MS found for C₂₈H₂₇ClFN₅O₅: (M+H)⁺: 568.1.

Example 258

The title compound was synthesized according to the procedure describedpreviously. MS found for C₂₆H₂₃ClFN₅O₅: (M+H)⁺: 540.1.

Example 259

The title compound was synthesized according to the procedure describedpreviously. MS found for C₂₉H₂₉ClFN₅O₅: (M+H)⁺: 582.2.

Example 260

The title compound was synthesized according to the procedure describedpreviously. MS found for C₂₇H₂₅ClN₅O₅: (M+H)⁺: 554.1.

Example 261 Step 1

To a solution of 2-amino-5-bromopyridine (882 mg, 5.1 mmol) intetrahydrofuran (5 ml) was added 0.5M potassium bis(trimethylsilyl)amidein toluene (20 ml, 10.1 mmol) dropwise at −78° C. After stirred foradditional 0.5 hr at −78° C., the mixture was added 5-chloroisatoicanhydride (1 g, 5.1 mmol) at −78° C. The mixture was warmed up to r.tgradually and stirred overnight. After concentrated, the crude waswashed with saturated ammonium chloride solution and extracted by ethylacetate. The organic layer was dried over magnesium sulfate andconcentrated to give(2-amino-5-bromophenyl)-N-(5-chloro(2-pyridyl))carboxamide as yellowsolid (1.54 g. 92%). MS found for C12H9BrClN3O M⁺=327, (M+2)⁺=329.

Step 2

To a solution of the compound of(2-amino-5-bromophenyl)-N-(5-chloro(2-pyridyl))carboxamide (1.33 g, 4.07mmol) in dichloromethane (10 ml) was added 4-cyanobenzoly chloride (808mg, 4.88 mmol) and pyridine (1 ml, 12.21 mmol). The mixture was stirredat r.t. overnight. The precipitate was filtered and washed with a littleamount of dichloromethane to giveN-{4-chloro-2-[N-(5-bromo(2-pyridyl))carbamoyl]phenyl}(4-cyanophenyl)carboxamideas yellow solid (1.36 g, 73%). MS found for C20H12BrClN4O2 M⁺=455,(M+2)⁺=457.

Step 3

To a solution of the compound ofN-{4-chloro-2-[N-(5-bromo(2-pyridyl))carbamoyl]phenyl}(4-cyanophenyl)carboxamide(1.36 g, 3 mmol) in anhydrous pyridine (20 ml) and triethyl amine (2 ml)was saturated with hydrogen sulfide gas at 0° C. The mixture was stirredat r.t. overnight. After concentrated, the residue was dissolved inanhydrous acetone (20 ml) and iodomethane (1.87 ml, 30 mmol) was added.The mixture was refluxed for 2 hrs. After concentrated, the residue wasdissolved in anhydrous methanol (20 ml) and a solution of 2Mdimethylamine (in THF) (15 ml, 30 mmol) and acetic acid (10 ml) inanhydrous methanol (5 ml) was added. The mixture was refluxed for 2 hrs.After concentrated, the crude residue was purified by RP-HPLC to givetarget as white solid (750 mg, 50%). MS found C22H19BrClN5O2 M⁺=500,(M+2)⁺=502.

Example 262 Step 1

To a solution of 2-amino-5-chloropyridine (787 mg, 6.1 mmol) intetrahydrofuran (5 ml) was added 0.5M potassium bis(trimethylsilyl)amidein toluene (20 ml, 10.1 mmol) dropwise at −78° C. After stirred foradditional 0.5 hr at −78° C., the mixture was added 5-chloroisatoicanhydride (1 g, 5.1 mmol) at −78° C. The mixture was warmed up to r.tgradually and stirred overnight. After concentrated, the crude waswashed with saturated ammonium chloride solution and extracted by ethylacetate. The organic layer was dried over magnesium sulfate andconcentrated to give(2-amino-5-chlorophenyl)-N-(5-chloro(2-pyridyl))carboxamide as yellowsolid (1.39 g. 99%). MS found for C12H9Cl2N3O M⁺=282, (M+2)⁺=284.

Step 2

A solution of 2-fluoro-4-cyanobenzoic acid (1 g, 6.06 mmol) in thionylchloride (5 ml) was refluxed for 2 hr. After concentration, the residuewas dissolved in dichloromethane (5 ml). And a solution of the compoundof (2-amino-5-chlorophenyl)-N-(5-chloro(2-pyridyl))carboxamide (1.2 g,4.25 mmol) in dichloromethane (10 ml) and pyridine (1.47 ml, 18.18 mmol)were added. The mixture was stirred at r.t. overnight. The precipitatewas filtered and washed with a little amount of dichloromethane to giveN-{4-chloro-2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}(2-fluoro-4-cyanophenyl)carboxamide(2.03 g, 78%). MS found for C20H11Cl2FN4O2 M⁺=429, (M+2)⁺=431.

Step 3

To a solution of the compound ofN-{4-chloro-2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}(2-fluoro-4-cyanophenyl)carboxamide(3 g, 7 mmol) in anhydrous pyridine (40 ml) and triethyl amine (4 ml)was saturated with hydrogen sulfide gas at 0° C. The mixture was stirredat r.t. overnight. After concentrated, the residue was dissolved inanhydrous acetone (60 ml) and iodomethane (4.36 ml, 70 mmol) was added.The mixture was refluxed for 2 hrs. After concentrated, the residue wasdissolved in anhydrous methanol (50 ml) and a solution of 2Mdimethylamine (in THF) (35 ml, 70 mmol) and acetic acid (30 ml) inanhydrous methanol (15 ml) was added. The mixture was refluxed for 2hrs. After concentrated, the crude residue was purified by RP-HPLC togive target as white solid (1.7 g, 50%). MS found C22H18Cl2FN5O2 M⁺=474,(M+2)⁺=476.

Examples 263-280

The following compounds were similarly prepared.

Examples 281-287

The following compounds were similarly prepared.

Example 288

Step 1: A solution of methyl 2-amino-5-nitrobenzoate (1 equiv) and4-cyanobenzoic acid (1 equiv) in pyridine was treated with POCl₃ (1.1equiv) for 1 h. The resulting mixture was quenched by slow addition ofwater, and extracted with EtOAc. The organic layer was dried over MgSO₄,filtered and flash chromatographied to give the desired product.

Step 2: A solution of 2-amino-5-bromopridine (45 mg, 4.0 equiv) in 5 mLof methylene chloride treated with AlMe₃ (2M in hexane, 0.65 mL, 20equiv) for 30 min was added the compound obtained in step 1 (0.064 mmol,1 equiv). The mixture was stirred at rt overnight, quenched withsaturated aqueous potassium sodium tartrate. The organic layer was driedover MgSO₄, filtered, evaporated and purified by column chromatographyto give the desired product.

Step 3: The product obtained in step 2 was subjected to standard Pinnerconditions to give the title compound after HPLC (C18 reversed phase,eluting with 0.5% TFA in H₂O/CH₃CN). MS (M+H)⁺: 467.

Example 289

This compound was prepared according to the procedure previouslydescribed. MS (M+H)⁺: 467.

Example 290-302

The following compounds were prepared according to the procedurepreviously described.

Example 303

Example 297 (1 equiv) in CH₂Cl₂ was treated with BBr₃ (4 equiv)overnight, quenched with ice water. HPLC (C18 reversed phase, elutingwith 0.5% TFA in H₂O/CH₃CN) gave the title compound. MS (M+H)⁺: 438.

Example 304-308

The following compounds were prepared according to the procedurepreviously described.

Example 309

This compound was prepared according to the procedure previouslydescribed. MS (M+H)⁺: 543.

Example 310-315

The following compounds were prepared according to the procedurepreviously described.

Example 316

The title compound was synthesized according to the procedure describedpreviously. ES-MS 417 (M+1).

Example 317

The title compound was synthesized according to the procedure describedpreviously. ES-MS 431 (M+1).

Example 318

The title compound was synthesized according to the procedure describedpreviously. ES-MS 404 (M+1).

Example 319

The title compound was synthesized according to the procedure describedpreviously. ES-MS 445 (M+1).

Example 320

Example 53 (15 mg) was refluxed in pyridine in the presence of 0.1 mL ofMeI overnight. The volatile was evaporated and the residue was purifiedby HPLC to give example 403. MS (M+H): 436.

Examples 321-322

The following compounds were prepared according to the procedurepreviously described.

Example 323

Compound 304 (20 mg) was dissolved in 10 mL of CH₂Cl₂ and was treatedwith 2 mL of BBr₃ (1N in CH₂Cl₂) overnight. The reaction was quenchedwith water and reverse phase HPLC gave the desired product. ES-MS 424(M+H).

Example 324-336

The following compounds were prepared according to the procedurepreviously described.

Example 337-344

The following compounds were prepared according to the procedurepreviously described.

Example 345-360

The following compounds were prepared according to the procedurepreviously described.

Example 361-390

The following compounds were prepared according to the procedurepreviously described.

Example 391-398

The following compounds were prepared according to the procedurepreviously described

Example 399

Step 1: A mixture of 4-cyanobenzaldehyde (1 equiv),4-chloro-2-(5-chloro-2-pyridinyl)amino-carbonyl aniline (1 equiv) andglacial acetic acid (10 equiv) in CH₂Cl₂ was stirred at rt for 30 min.NaBH(OAc)₃ (3 equiv) was added at once and the mixture was stirredovernight. The reaction was quenched with water and the organic layerwas washed with brine and dried over Na₂SO₄. Column separation oversilica gel gave the desired product.

Step 2: A solution of the compound obtained in step 1 (15 mg) inanhydrous pyridine (10 mL) and triethyl amine (2 mL) was saturated withhydrogen sulfide gas at 0° C. The mixture was stirred at rt overnight.After concentration, the residue was dissolved in anhydrous acetone (10mL) and iodomethane (1 mL) was added. The mixture was refluxed for 2hrs. After concentration, the residue was dissolved in anhydrousmethanol (5 mL) and a solution of pyrrolidine (0.5 mL) and acetic acid(0.5 mL) in anhydrous methanol (5 ml) was added. The mixture wasrefluxed for 15 min. After concentrated, the crude residue was purifiedby RP-HPLC to give target. MS (M+H) 468.

Examples 400-426

The following compounds were prepared according to the procedurepreviously described.

Example 427

Step 1: A mixture of 4-cyanobenzyl bromide (1 equiv), methyl2-hydroxybenzoate (1 equiv) and cesium carbonate (10 equiv) in DMF wasstirred at rt overnight. The mixture was then diluted with EtOAc, washedwith water, dried over Na₂SO₄, filtered and evaporated to give theproduct.

Step 2: A solution of the compound obtained in step 1 (1 equiv) in MeOHwas treated with 1N LiOH (2.2 equiv) for 1 h. After removal of methanoland acidifying with 1N HCl to PH ˜1, the mixture was extracted withEtOAc. The organic layer was dried over Na₂SO₄, filtered and evaporatedto give the product.

Step 3: A solution of the compound obtained in step 2 (1 equiv) indichloromethane was treated with oxalyl chloride (3 equiv) and 2 dropsof DMF at rt for 3 h. The volatile was evaporated and the residue wasredissolved in methylenechloride. To the solution was added2-amino-5-chloropyridine (1 equiv) and pyridine (5 equiv). The mixturewas stirred at rt for 2 h, washed with water, dried over Na₂SO₄,filtered and evaporated to give the product.

Step 2: A solution of the compound obtained in step 3 (15 mg) inanhydrous pyridine (10 mL) and triethyl amine (2 mL) was saturated withhydrogen sulfide gas at 0° C. The mixture was stirred at rt overnight.After concentration, the residue was dissolved in anhydrous acetone (10mL) and iodomethane (1 mL) was added. The mixture was refluxed for 2hrs. After concentration, the residue was dissolved in anhydrousmethanol (5 mL) and a solution of pyrrolidine (0.5 mL) and acetic acid(0.5 mL) in anhydrous methanol (5 ml) was added. The mixture wasrefluxed for 15 min. After concentrated, the crude residue was purifiedby RP-HPLC to give target. MS (M+H) 435.

Examples 428-431

The following compounds were similarly prepared.

Example 432

Step 1: A solution of 2-carboxybenzaldehyde (1 equiv) in dichloromethanewas treated with oxalyl chloride (3 equiv) and 2 drops of DMF at rt for3 h. The volatile was evaporated and the residue was redissolved inmethylenechloride. To the solution was added 2-amino-5-chloropyridine (1equiv) and pyridine (5 equiv). The mixture was stirred at rt for 2 h,washed with water, dried over Na₂SO₄, filtered and evaporated to givethe product.

Step 2: A mixture of the compound obtained in step 1 (1 equiv),4-cyanoaniline (1 equiv) and glacial acetic acid (10 equiv) in CH₂Cl₂was stirred at rt for 30 min NaBH(OAc)₃ (3 equiv) was added at once andthe mixture was stirred overnight. The reaction was quenched with waterand the organic layer was washed with brine and dried over Na₂SO₄.Column separation over silica gel gave the desired product.

Step 3: A solution of the compound obtained in step 2 (15 mg) inanhydrous pyridine (10 mL) and triethyl amine (2 mL) was saturated withhydrogen sulfide gas at 0° C. The mixture was stirred at rt overnight.After concentration, the residue was dissolved in anhydrous acetone (10mL) and iodomethane (1 mL) was added. The mixture was refluxed for 2hrs. After concentration, the residue was dissolved in anhydrousmethanol (5 mL) and a solution of pyrrolidine (0.5 mL) and acetic acid(0.5 mL) in anhydrous methanol (5 ml) was added. The mixture wasrefluxed for 15 min. After concentrated, the crude residue was purifiedby RP-HPLC to give target. MS (M+H) 434.

Examples 433-437

The following compounds were similarly prepared.

Example 438

Step 1: A mixture of 4-chloromethylbemzoyl chloride (1 equiv),4-chloro-2-(5-chloro-2-pyridinyl)amino-carbonyl aniline (1 equiv) andpyridine (5 equiv) in CH₂Cl₂ was stirred at reflux for 4 h. The reactionwas cooled to rt and the organic layer was washed with brine and driedover Na₂SO₄. Column separation over silica gel gave the desired product(˜20% yield).

Step 2: A solution of the compound obtained in step 1 (15 mg) in DMF (1mL) was treated with pyrrolidine (1 mL) at rt overnight. After removingthe volatile, the crude residue was purified by RP-HPLC to give thetarget. MS (M+H) 469.

Example 439-458

The following compounds were prepared according to the procedurepreviously described.

Example 459-494

The following compounds were prepared according to the procedurepreviously described.

Example 495N-{2-[N-(5-chloro(2-pyridyl))carbamoyl](3-thienyl)}[4-(1-methyl(2-imidazolin-2-yl))phenyl]carboxamide

Preparation of methyl3-[(4-cyanophenyl)carbonylamino]thiophene-2-carboxylate

A mixture of 4-cyanobenzoyl chloride (1.0500 g, 6.4 mmol), methyl3-aminothiophenecarboxylate (1.0000 g, 6.4 mmol), and triethylamine (1mL, 7.0 mmol) in dichloromethane was stirred at room temperature for 18hours. The mixture was poured into a separatory funnel and washed by 1 NHCl. The organic layers were combined, dried over MgSO4, concentrated invacuo, and chromatographed through a silica gel column to give the titlecompound 1.6588 g (91%). ES-MS 287 (M+1).

Preparation ofN-{2-[N-(5-chloro(2-pyridyl))carbamoyl](3-thienyl)}(4-cyanophenyl)carboxamide

A portion of 2-amino-5-chloropyridine (68.6 mg, 0.5 mmol) was treatedwith AlMe3 (0.8 mL, 1.6 mmol), followed by adding the product from stepA (160 mg, 0.5 mmol). The mixture was stirred at room temperature for 18hours. The excess of AlMe3 was killed by 1N HCl solution. The organiclayers were combined, dried over MgSO4, concentrated in vacuo, andchromatographed through a silica gel column to give the title compound0.1528 g (80%). ES-MS 383 (M+1).

A mixture of the product from step B (0.1528 g, 0.4 mmol) and EtOHsaturated with HCl was stirred at room temperature for 18 hours. Thesolvent was removed by a rotovap. The crude oil was treated with 2 mLN-methylethylenediamine for 2 hours until the reaction was complete.Prep HPLC was used to purity the final product. It gave 0.1537 g (88%).ES-MS 440 (M+1).

Example 496{4-[(dimethylamino)iminomethyl]phenyl}-N-{2-[N-(5-chloro(2-pyridyl))carbamoyl](3-thienyl)}carboxamide

The title compound was obtained according to the procedure previouslydescribed. ES-MS 428 (M+1).

Example 4974-(N-{2-[N-(5-chloro-2-pyridyl)carbamoyl]-3-thienyl}carbamoyl)benzenecarboxamidine

The title compound was obtained according to the procedure previouslydescribed. ES-MS 400 (M+1).

Example 498N-{2-[N-(5-chloro(2-pyridyl))carbamoyl](3-thienyl)}[4-(iminopiperidylmethyl)-phenyl]carboxamide

The title compound was obtained according to the procedure previouslydescribed. ES-MS 468 (M+1).

Example 499N-{2-[N-(5-chloro(2-pyridyl))carbamoyl](3-thienyl)}[4-(iminopyrrolidinylmethyl)-phenyl]carboxamide

The title compound was obtained according to the procedure previouslydescribed. ES-MS 454 (M+1).

Example 500N-{2-[N-(5-chloro(2-pyridyl))carbamoyl](3-thienyl)}[4-(iminomorpholin-4-ylmethyl)phenyl]carboxamide

The title compound was obtained according to the procedure previouslydescribed. ES-MS 470 (M+1).

Example 501N-{2-[N-(5-chloro(2-pyridyl))carbamoyl](3-thienyl)}[4-(imino-1,4-thiazaperhydroin-4-ylmethyl)phenyl]carboxamide

The title compound was obtained according to the procedure previouslydescribed. ES-MS 486 (M+1).

Example 502[4-(azaperhydroepinyliminomethyl)phenyl]-N-{2-[N-(5-chloro(2-pyridyl))carbamoyl](3-thienyl)}carboxamide

The title compound was obtained according to the procedure previouslydescribed. ES-MS 482 (M+1).

Example 503

N-{2-[N-(5-chloro(2-pyridyl))carbamoyl](3-thienyl)}{4-[imino(2-methylpyrrolidinyl)methyl]phenyl}carboxamide

The title compound was obtained according to the procedure previouslydescribed. ES-MS 468 (M+1).

Example 504N-{2-[N-(5-chloro(2-pyridyl))carbamoyl](3-thienyl)}{4-[imino(methylamino)methyl]-phenyl}carboxamide

The title compound was obtained according to the procedure previouslydescribed.

Example 505N-{2-[N-(5-chloro(2-pyridyl))carbamoyl](3-thienyl)}[4-(3-methyl(3,4,5,6-tetrahydropyrimidin-2-yl))phenyl]carboxamide

The title compound was obtained according to the procedure previouslydescribed. ES-MS 414 (M+1).

Example 506N-{2-[N-(5-chloro(2-pyridyl))carbamoyl](3-thienyl)}[4-((hydroxyamino)iminomethyl)-phenyl]carboxamide

The title compound was obtained according to the procedure previouslydescribed. ES-MS 416 (M+1).

Example 507N-{2-[N-(5-bromo(2-pyridyl))carbamoyl](3-thienyl)}[4-(1-methyl(2-imidazolin-2-yl))phenyl]carboxamide

The title compound was obtained according to the procedure previouslydescribed. ES-MS 484 (M+1).

Example 5084-(N-{2-[N-(5-bromo-2-pyridyl)carbamoyl]-3-thienyl}carbamoyl)benzenecarboxamidine

The title compound was obtained according to the procedure previouslydescribed. ES-MS 444 (M+1).

Example 509N-{2-[N-(5-bromo(2-pyridyl))carbamoyl](3-thienyl)}[4-(iminopyrrolidinylmethyl)phenyl]carboxamide

The title compound was obtained according to the procedure previouslydescribed. ES-MS 494 (M+1).

Example 510N-{2-[N-(5-bromo(2-pyridyl))carbamoyl](3-thienyl)}[4-(iminopiperidylmethyl)phenyl]carboxamide

The title compound was obtained according to the procedure previouslydescribed. ES-MS 512 (M+1).

Example 511N-{2-[N-(5-bromo(2-pyridyl))carbamoyl](3-thienyl)}[4-(iminomorpholin-4-ylmethyl)phenyl]carboxamide

The title compound was obtained according to the procedure previouslydescribed. ES-MS 514 (M+1).

Example 512N-{2-[N-(5-bromo(2-pyridyl))carbamoyl](3-thienyl)}[4-(imino-1,4-thiazaperhydroin-4-ylmethyl)phenyl]carboxamide

The title compound was obtained according to the procedure previouslydescribed. ES-MS 530 (M+1).

Example 513N-{3-[N-(5-chloro(2-pyridyl))carbamoyl](2-thienyl)}[4-(iminopyrrolidinylmethyl)phenyl]carboxamide

The title compound was obtained according to the procedure previouslydescribed. ES-MS 454 (M+1).

Example 514N-{3-[N-(5-chloro(2-pyridyl))carbamoyl](2-thienyl)}[4-(1-methyl(2-imidazolin-2-yl))phenyl]carboxamide

The title compound was obtained according to the procedure previouslydescribed. ES-MS 440 (M+1).

Examples 515-520

The following examples are prepared according to the procedurepreviously described.

Example 521N-{2-[N-(5-chloro(2-pyridyl))carbamoyl](3-thienyl)}[4-(2-sulfamoylphenyl)phenyl]carboxamide

A solution of 4-(2-{[tert-butyl)amino]sulfonyl}phenyl)benzoyl chloride(1 equiv), 3-amino-2-(4-chloro-2-pyridinyl)aminocarbonyl thiophene (1equiv), pyridine (5 equiv) in dichloromethane was stirred at rtovernight. The mixture was diluted with dichloromethane, washed withwater, dried over Na2SO4, filtered and evaporated. The residue wasrefluxed with 1 mL of TFA for 2 h. After evaporation, reverse phase HPLCgave the title product. ES-MS 513 (M+1).

Example 522N-{2-[N-(5-bromo(2-pyridyl))carbamoyl](3-thienyl)}[4-(2-sulfamoylphenyl)phenyl]carboxamide

The title compound was obtained according to the procedure previouslydescribed. ES-MS 556 (M+1).

Example 523N-(4-methoxyphenyl)-N′-(4-[(2-aminosulfonyl)phenyl]phenyl)-maleamicamide

A. Preparation ofN-(4-methoxyphenyl)-N′-(4-[(2-tert-butylaminosulfonyl)phenyl]phenyl)-maleamicamide

To a solution of commercially available N-(4-methoxyphenyl)maleamic acid(100 mg, 0.452 mmol), triethylamine (0.126 mL, 0.906 mmol) and4-(2-tert-butylaminosulfonylphenyl)aniline (138 mg, 0.454 mmol) inanhydrous DMF (5 mL), BOP (260 mg, 0.588 mmol) was added. The mixturewas stirred at room temperature overnight. Water and EtOAc were added.The organic phase was separated, washed with H2O, then with 5% NaHCO3,dried over Na2SO4, concentrated in vacuo. The residue was purified byHPLC using a gradient of 20% CH3CN in H2O (containing 0.1% TFA) to 100%CH3CN over 80 min. Fractions containing the desired product were pooled,and lyophilized to give a powder (70 mg, yield: 31%). MS 508 (M+H).

B. Preparation ofN-(4-methoxyphenyl)-N′-(4-[(2-aminosulfonyl)phenyl]phenyl)-maleamicamide

The compoundN-(4-methoxyphenyl)-N′-(4-[(2-tert-butylaminosulfonyl)phenyl]phenyl)-maleamicamide (40 mg, 79 μmol) was dissolved in TFA (3 mL). It was allowed tostand at room temperature overnight. TFA was removed in vacuo. Theresidue was purified by HPLC using a gradient of 5% CH3CN in H2O(containing 0.1% TFA) to 95% CH3CN over 60 min. Fractions containing thedesired product were pooled, and lyophilized to give a powder (18 mg,yield: 51%). MS 452 (M+H) and 474 (M+Na). ¹H NMR (CDCl3) δ 11.40 (br.s,1H), 10.28 (br.s, 1H), 8.12 (d, 1H, J=8 Hz), 7.72 (d, 2H, J=8 Hz),7.60-7.20 (m, 9H), 6.86 (AB type, 2H), 6.45 (br.s, 2H), 3.79 (s, 3H).

Example 524N-(4-bromophenyl)-N′-(4-[(2-aminosulfonyl)phenyl]phenyl)-maleamic amide

A. Preparation of N-(4[(2-tert-butylaminosulfonyl)phenyl]phenyl)maleamicmethyl ester

To a solution of commercially available maleic acid monomethyl ester(277 mg, 2.13 mmol), 4-(2-tert-butylaminosulfonylphenyl)aniline (648 mg,2.13 mmol) and triethylamine (0.593 mL, 4.26 mmol) in CH2Cl2 (20 mL),BOP (1.13 g, 2.55 mmol) was added. The mixture was stirred at roomtemperature overnight. More maleic acid monomethyl ester (50 mg, 0.385mmol) was added. It was stirred for 3 hours. The CH2Cl2 solution wasthen washed with sat. NaHCO3, 1N HCl and sat. NaCl. The solution wasdried over Na2SO4, concentrated in vacuo. The residue was purified by asilica gel column using a gradient of 10-40% EtOAc in hexane assolvents, to give the titled compound (360 mg, yield: 41%). MS 361(M+H-^(t)Bu) and 439 (M+Na).

B. Preparation ofN-(4-bromophenyl)-N′-(4-[(2-aminosulfonyl)phenyl]phenyl)-maleamic amide

To a solution of 4-bromoaniline (93 mg, 0.543 mmol) in CH2Cl2 (5 mL) atroom temperature, trimethylaluminum (0.82 mL, 2.0 M in hexane, 1.64mmol) was added dropwise. After the solution was stirred for 30 min atroom temperature, compoundN-(4-[(2-tert-butylaminosulfonyl)phenyl]phenyl)maleamic methyl ester(113 mg, 0.272 mmol) was added. The mixture was stirred at roomtemperature for 2 days. The solution was neutralized with 1N HCl to pH2-3. Water and CH2Cl2 were added, and organic phase was separated, driedover Na2SO4, concentrated in vacuo. The residue was dissolved in TFA (4mL). It was allowed to stand at room temperature overnight. TFA wasremoved in vacuo. The residue was purified by HPLC using a gradient of5% CH3CN in H2O (containing 0.1% TFA) to 95% CH3CN over 60 min.Fractions containing the desired product were pooled, and lyophilized togive a powder (8 mg, yield: 6%). MS 500 and 502 (M+H), 522 and 524(M+Na). ¹H NMR (CD3OD) δ 8.09 (d, 1H, J=8 Hz), 7.68 (d, 2H, J=8 Hz),7.64-7.28 (m, 9H), 6.45 (AB type, 2H).

Examples 525 and 526 Preparation ofN¹-(5-bromopyridin-2-yl)-N⁴-(4-[(2-aminosulfonyl)phenyl]phenyl)-2-methylmaleamicamide andN¹-(5-bromopyridin-2-yl)-N⁴-(4-[(2-aminosulfonyl)phenyl]phenyl)-3-methylmaleamicamide

A. Preparation of N-(5-bromopyridin-2-yl)-methylmaleimide

A mixture of citraconic anhydride (1.00 mL, 11.1 mmol) and2-amino-5-bromopyridine (1.93 g, 11.2 mmol) in toluene (60 mL) washeated to reflux overnight. The solution was cooled down, filtered. Thefiltrate was concentrated in vacuo to give a solid (2.10 g, yield: 71%).MS 267 and 269 (M+H).

B. Preparation ofN¹-(5-bromopyridin-2-yl)-N⁴-(4-[(2-aminosulfonyl)phenyl]phenyl)-2-methylmaleamicamide andN¹-(5-bromopyridin-2-yl)-N⁴-(4-[(2-aminosulfonyl)phenyl]phenyl)-3-methylmaleamicamide

To the solution of 4-(2-aminosulfonylphenyl)aniline (0.170 g, 0.685mmol) in CH2Cl2 (10 mL) at room temperature, trimethylaluminum (2.0 M inhexane, 2.00 mL, 4.00 mmol) was added dropwise, during which time, whitegel-like precipitates came out the solution. It was stirred for 30 min.A solution of N-(5-bromopyridin-2-yl)-methylmaleimide (0.122 g, 0.457mmol) in CH2Cl2 (5 mL) was added. It was stirred for 1 hour, duringwhich time the precipitates started to dissolve, and the solution becameclear. It was stirred for another 2 hours. 1N HCl was added toneutralize the solution to pH 2-3, which resulted in precipitation. Theprecipitates were collected by filtration, dried on vacuum. Theprecipitates (75 mg, yield: 32%) were a mixture of 2-methyl and3-methylmaleamic amide isomers in a ratio of 1:5. MS 515 and 517 (M+H),537 and 539 (M+Na).

Example 527

A solution of 3-amino-4-[(5-chloro-2-pyridinyl)aminocarbonyl]pyrazole (1equiv) and 4-cyanobenzoic acid (1 equiv) in pyridine was treated withPOCl₃ (1.1 equiv) for 30 min. The resulting mixture was quenched by slowaddition of water, and extracted with CH₂Cl₂ and dried over MgSO₄. Afterevaporation, the residue was trituated with a small amount of CH₂Cl₂ andEtOAc. The solid on the glass wall was then subjected to standard Pinnerconditions to give desired product. MS (M+H)⁺: 426.

Examples 528-538

The following examples were prepared according to the procedurepreviously described.

Example 539

Step 1: A solution of 3-amino-4-ethoxycarbonyl-pyrazole (1 equiv) and4-cyanobenzoic acid (1 equiv) in pyridine was treated with POCl₃ (1.1equiv) for 1 h. The resulting mixture was quenched by slow addition ofwater, extracted with CH₂Cl₂, dried over MgSO₄, and purified by columnchromatography to give the desired product.

Step 2: The compound obtained in step 1 (1 equiv) in DMF was treatedwith NaSMe (10 equiv) at 65° C. overnight. The resulting mixture wasquenched by slow addition of water, and acidified with 1 N HCl,extracted with EtOAc, and dried over MgSO₄. The acid was reflux inexcess SOCl₂ for 2 h. The volatile was removed on rotovap, and theresidue was redissolved in pyridine, refluxed overnight in the presenceof DMAP (1 equiv) and 4-chloroaniline (10 equiv). The resulting mixturewas quenched by slow addition of water, and extracted with CH₂Cl₂ anddried over MgSO₄. After evaporation, the residue was trituated with asmall amount of CH₂Cl₂ and EtOAc. The solid on the glass wall was thensubjected to standard Pinner conditions to give desired product. MS(M+H)⁺: 425.

Example 540

Similarly prepared as Example 350. MS (M+H)⁺: 443.

Examples 541-551

The following examples were prepared according to the procedurepreviously described.

Examples 552-559

The following examples were prepared according to the procedurepreviously described.

Example 560

The title compound was synthesized according to the procedure describedpreviously. ES-MS 514 (M+1).

Example 561

The title compound was synthesized according to the procedure describedpreviously. ES-MS 558 (M+1).

Example 562-585

The following compounds were prepared according to the procedurepreviously described.

Example 5863-(2-(4-[(2-aminosulfonyl)phenyl]benzoylamino)phenoxy)benzamidine

Step 1: To a solution of 2-fluoro nitrobenzene (1.41 g, 10 mmol, 1.0equiv) and 3-hydroxybenzonitrile (1.19 g, 1.0 equiv) in 10 mL of DMF wasadded K₂CO₃ (2.76 g, 2 equiv). After stirring at 60° C. for 3 h, themixture was diluted with EtOAc and washed with H₂O. The organic layerwas dried over MgSO₄, filtered and evaporated to give3-(2-nitrophenoxy)benzonitrile (2.38 g, 99%). MS found for C₁₃H₉N₂O₃(M+H)⁺: 241.

Step 2: A solution of 3-(2-nitrophenoxy)benzonitrile (1.21 g, 5 mmol,1.0 equiv) in 30 mL of EtOH was treated with SnCl₂.2H₂O (3.38 g, 3equiv) at reflux for 4 h. The volatile was evaporated and the residuewas redissolved in EtOAc, washed with saturated aqueous NaHCO₃ and 1NNaOH. The organic layer was dried over MgSO₄, filtered and evaporated togive 3-(2-aminophenoxy)benzonitrile (1.04 g, 99%). MS found forC₁₃H₁₁N₂O (M+H)⁺: 211.

Step 3: A mixture of 3-(2-aminophenoxy)benzonitrile (210 mg, 1 mmol, 1.0equiv), 4-[(2-t-butylaminosulfonyl)phenyl]benzoic acid (330 mg, 1equiv), Bop reagent (880 mg, 2 equiv) and TEA (1.39 mL, 10 equiv) in 3mL of DMF was stirred at rt overnight. The mixture was diluted withEtOAc, washed with H₂O. The organic layer was dried over MgSO₄, filteredand evaporated. Flash chromatography on silica gel gave3-(2-(4-[(2-t-butylaminosulfonyl)phenyl]benzoylamino)phenoxy)benzonitrile(300 mg, 57%). MS found for C₃₀H₂₈N₃O₄S (M+H)⁺: 526.

Step 4: A stream of HCl(g) was bubbled through a 0° C. solution of3-(2-(4-[(2-t-butylaminosulfonyl)phenyl]benzoylamino)phenoxy)benzonitrile(53 mg, 0.1 mmol) in 5 mL of methanol until saturation. The mixture wasstirred at rt overnight and evaporated. The resulting residue wastreated with ammonium acetate (39 mg, 5 equiv) in 10 ml methanol atreflux temperature for 2 h. The solvent was removed at reduced pressureand the crude benzamidine was purified by HPLC (C18 reversed phase)eluting with 0.5% TFA in H₂O/CH₃CN to give3-(2-(4-[(2-aminosulfonyl)phenyl]benzoylamino) phenoxy)benzamidine (40mg, 83%). MS found for C₂₆H₂₃N₄O₄S (M+H)⁺: 487.

Example 5873-(4-fluoro-2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy)benzamidine

Step 1: A mixture of 3-(2-amino-4-fluorophenoxy)benzonitrile (230 mg, 1mmol, 1.0 equiv), 4-[(2-t-butylaminosulfonyl)phenyl]benzoic chloride(349 mg, 1 equiv), pyridine (3 mL) in 10 mL of dichloromethane wasstirred at rt overnight, washed with H₂O. The organic layer was driedover MgSO₄, filtered and evaporated. Flash chromatography on silica gelgave3-(4-fluoro-2-(4-[(2-t-butylaminosulfonyl)phenyl]phenylcarbonylamino)phenoxy)benzonitrile(495 mg, 91%). MS found for C₃₀H₂₇FN₃O₄S (M+H)⁺: 544.

Step 2: A stream of HCl(g) was bubbled through a 0° C. solution of3-(4-fluoro-2-(4-[2-t-butylaminosulfonyl)phenyl]phenylcarbonylamino)phenoxy)benzonitrile(55 mg, 0.1 mmol) in 5 mL of methanol until saturation. The mixture wasstirred at rt overnight and evaporated. The resulting residue wastreated with ammonium acetate (39 mg, 5 equiv) in 10 ml methanol atreflux temperature for 2 h. The solvent was removed at reduced pressureand the crude benzamidine was purified by HPLC (C18 reversed phase)eluting with 0.5% TFA in H₂O/CH₃CN to give3-(4-fluoro-2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy)benzamidine(39 mg, 77%). MS found for C₂₆H₂₂FN₄O₄S (M+H)⁺: 505.

Example 5883-(4-trifluoromethyl-2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy)benzamidine

Step 1: A mixture of 3-(2-amino-4-trifluoromethylphenoxy)benzonitrile(280 mg, 1 mmol, 1.0 equiv), 4-[(2-t-butylaminosulfonyl)phenyl]benzoicchloride (349 mg, 1 equiv), pyridine (3 mL) in 10 mL of dichloromethanewas stirred at rt overnight, washed with H₂O. The organic layer wasdried over MgSO₄, filtered and evaporated. Flash chromatography onsilica gel gave3-(4-trifluoromethyl-2-(4-[(2-t-butylaminosulfonyl)phenyl]phenylcarbonylamino)phenoxy)benzonitrile(529 mg, 89%). MS found for C₃₁H₂₇F₃N₃O₄S (M+H)⁺: 594.

Step 2: A stream of HCl(g) was bubbled through a 0° C. solution of3-(4-trifluoromethyl-2-(4-[(2-t-butylaminosulfonyl)phenyl]phenylcarbonylamino)phenoxy)benzonitrile(59 mg, 0.1 mmol) in 5 mL of methanol until saturation. The mixture wasstirred at rt overnight and evaporated. The resulting residue wastreated with ammonium acetate (39 mg, 5 equiv) in 10 ml methanol atreflux temperature for 2 h. The solvent was removed at reduced pressureand the crude benzamidine was purified by HPLC (C18 reversed phase)eluting with 0.5% TFA in H₂O/CH₃CN to give3-(4-trifluoromethyl-2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy)benzamidine(35 mg, 63%). MS found for C₂₇H₂₂F₃N₄O₄S (M+H)⁺: 555.

Example 5893-(4-methylsulfonyl-2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy)benzamidine

Step 1: A mixture of 3-(2-amino-4-methylsulfonylphenoxy)benzonitrile(290 mg, 1 mmol, 1.0 equiv), 4-[(2-t-butylaminosulfonyl)phenyl]benzoicchloride (349 mg, 1 equiv), pyridine (3 mL) in 10 mL of dichloromethanewas stirred at rt overnight, washed with H₂O. The organic layer wasdried over MgSO₄, filtered and evaporated. Flash chromatography onsilica gel gave3-(4-methylsulfonyl-2-(4-[(2-t-butylaminosulfonyl)phenyl]phenylcarbonylamino)phenoxy)benzonitrile(429 mg, 71%). MS found for C₃₁H₃₀N₃O₆S₂ (M+H)⁺: 604.

Step 2: A stream of HCl(g) was bubbled through a 0° C. solution of3-(4-methylsulfonyl-2-(4-[(2-t-butylaminosulfonyl)phenyl]phenylcarbonylamino)phenoxy)benzonitrile(60 mg, 0.1 mmol) in 5 mL of methanol until saturation. The mixture wasstirred at rt overnight and evaporated. The resulting residue wastreated with ammonium acetate (39 mg, 5 equiv) in 10 ml methanol atreflux temperature for 2 h. The solvent was removed at reduced pressureand the crude benzamidine was purified by HPLC (C18 reversed phase)eluting with 0.5% TFA in H₂O/CH₃CN to give3-(4-methylsulfonyl-2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy)benzamidine(27 mg, 47%). MS found for C₂₇H₂₅N₄O₆S₂ (M+H)⁺: 565.

Examples 590-593

The following compounds were prepared using the procedure previouslydescribed.

Example 5943-(5-hydroxy-2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy)benzamidine

A solution of3-(5-methoxy-2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy)benzamidine(52 mg, 0.1 mmol, 1 equiv) in 5 mL of methylene chloride was treatedwith BBr₃ (1 M in dichloromethane, 0.5 mL, 5 equiv) overnight. Thereaction was quenched with water carefully and after the volatile wasevaporated, the aqueous residue was purified by HPLC (C18 reversedphase) eluting with 0.5% TFA in H₂O/CH₃CN to give3-(5-hydroxy-2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy)benzamidine.(41 mg, 82%). MS found for C₂₆H₂₃N₄O₆S (M+H)⁺: 503.

Example 5953-(4-methoxycarbonyl-2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy)benzamidine

Step 1: A mixture of 3-(2-amino-4-methoxycarbonylphenoxy)benzonitrile(270 mg, 1 mmol, 1.0 equiv), 4-[(2-t-butylaminosulfonyl)phenyl]benzoicchloride (349 mg, 1 equiv), pyridine (3 mL) in 10 mL of dichloromethanewas stirred at rt overnight, washed with H₂O. The organic layer wasdried over MgSO₄, filtered and evaporated. Flash chromatography onsilica gel gave3-(4-methoxycarbonyl-2-(4-[(2-t-butylaminosulfonyl)phenyl]phenylcarbonylamino)phenoxy)benzonitrile(502 mg, 86%). MS found for C₃₂H₃₀N₃O₆S (M+H)⁺: 584.

Step 2: A stream of HCl(g) was bubbled through a 0° C. solution of3-(4-methoxycarbonyl-2-(4-[(2-t-butylaminosulfonyl)phenyl]phenylcarbonylamino)phenoxy)benzonitrile(58 mg, 0.1 mmol) in 5 mL of methanol until saturation. The mixture wasstirred at rt overnight and evaporated. The resulting residue wastreated with ammonium acetate (39 mg, 5 equiv) in 10 ml methanol atreflux temperature for 2 h. The solvent was removed at reduced pressureand the crude benzamidine was purified by HPLC (C18 reversed phase)eluting with 0.5% TFA in H₂O/CH₃CN to give3-(4-methoxycarbonyl-2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy)benzamidine(29.5 mg, 54%). MS found for C₂₈H₂₅N₄O₆S (M+H)⁺: 545.

Example 5963-(4-hydroxycarbonyl-2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy)benzamidine

A solution of3-(4-methoxycarbonyl-2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy)benzamidine(10.9 mg, 0.02 mmol, 1.0 equiv) in 5 mL of methanol was treated with 1NLiOH (2 mL) at rt for 2 h. Methanol was evaporated, the aqueous residuewas subjected to HPLC with 0.5% TFA in H₂O/CH₃CN to give3-(4-hydroxycarbonyl-2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy)benzamidine(8.9 mg, 84%). MS found for C₂₇H₂₃N₄O₆S (M+H)⁺: 531.

Example 5973-(2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenylamino)benzamidine

Step 1: A mixture of 3-(2-amino-phenylamino)benzonitrile (196 mg, 1mmol, 1.0 equiv), 4-[(2-t-butylaminosulfonyl)phenyl]benzoic chloride(349 mg, 1 equiv), pyridine (3 mL) in 10 mL of dichloromethane wasstirred at rt overnight, washed with H₂O. The organic layer was driedover MgSO₄, filtered and evaporated. Flash chromatography on silica gelgave3-(2-(4-[(2-t-butylaminosulfonyl)phenyl]phenylcarbonylamino)phenylamino)benzonitrile(226 mg, 43%). MS found for C₃₀H₂₉N₄O₃S (M+H)⁺: 525.

Step 2: A stream of HCl(g) was bubbled through a 0° C. solution of3-(2-(4-[(2-t-butylaminosulfonyl)phenyl]phenylcarbonylamino)phenylamino)benzonitrile(53 mg, 0.1 mmol) in 5 mL of methanol until saturation. The mixture wasstirred at rt overnight and evaporated. The resulting residue wastreated with ammonium acetate (39 mg, 5 equiv) in 10 ml methanol atreflux temperature for 2 h. The solvent was removed at reduced pressureand the crude benzamidine was purified by HPLC (C18 reversed phase)eluting with 0.5% TFA in H₂O/CH₃CN to give3-(2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenylamino)benzamidine(27 mg, 55%). MS found for C₂₆H₂₄N₅O₃S (M+H)⁺: 486.

Example 5987-(2-(4-[(2-aminosulfonyl)phenyl]benzoylamino)phenoxy)-1-aminoisoquinoline

Step 1: A mixture of 7-(2-aminophenoxy)isoquinoline (237 mg, 1 mmol, 1.0equiv), 4-[(2-t-butylaminosulfonyl)phenyl]benzoic acid (330 mg, 1equiv), Bop reagent (880 mg, 2 equiv) and TEA (1.39 mL, 10 equiv) in 3mL of DMF was stirred at rt overnight. The mixture was diluted withEtOAc, washed with H₂O. The organic layer was dried over MgSO₄, filteredand evaporated. Flash chromatography on silica gel gave7-(2-(4-[(2-t-butylaminosulfonyl)phenyl]benzoylamino)phenoxy)isoquinoline(469 mg, 85%). MS found for C₃₂H₃₀N₃O₄S (M+H)⁺: 552.

Step 2: A solution of7-(2-(4-[(2-t-butylaminosulfonyl)phenyl]benzoylamino)phenoxy)isoquinoline(110 mg, 0.2 mmol, 1 equiv) in 5 mL of acetone was treated with mCPBA(113 mg, 57%, 1.5 equiv) until HPLC showed complete reaction. Acetonewas evaporated, the residue was partitioned between methylene chlorideand saturated aqueous NaHCO₃. The organic layer was dried over MgSO₄ andused in the next step directly.

Step 3: The compound obtained in step 2 in 5 mL of pyridine was treatedwith tosyl chloride (46 mg, 1.2 equiv) at rt overnight and pyridine wasremoved under reduced pressure. The residue was reacted with 5 mL ofethanolamine for 12 h, and partitioned between methylene chloride andwater. The organic layer was dried over MgSO₄, filtered, evaporated andrefluxed in 3 mL of trifluoroacetic acid for 30 min. After removing TFA,the crude was purified by HPLC (C18 reversed phase) eluting with 0.5%TFA in H₂O/CH₃CN to give7-(2-(4-[(2-aminosulfonyl)phenyl]benzoylamino)phenoxy)-1-aminoisoquinoline(43 mg, 42%). MS found for C₂₈H₂₃N₄O₄S (M+H)⁺: 511.

Example 5997-(2-(4-[(2-aminosulfonyl)phenyl]benzoylamino)-4-fluorophenoxy)1-aminoisoquinoline

Step 1: A mixture of 7-(2-amino-4-fluorophenoxy)isoquinoline (255 mg, 1mmol, 1.0 equiv), 4-[(2-t-butylaminosulfonyl)phenyl]benzoic acid (330mg, 1 equiv), Bop reagent (880 mg, 2 equiv) and TEA (1.39 mL, 10 equiv)in 3 mL of DMF was stirred at rt overnight. The mixture was diluted withEtOAc, washed with H₂O. The organic layer was dried over MgSO₄, filteredand evaporated. Flash chromatography on silica gel gave7-(2-(4-[(2-t-butylaminosulfonyl)phenyl]benzoylamino)-4-fluorophenoxy)isoquinoline(467 mg, 82%). MS found for C₃₂H₂₉FN₃O₄S (M+H)⁺: 570.

Step 2: A solution of7-(2-(4-[(2-t-butylaminosulfonyl)phenyl]benzoylamino)-4-fluorophenoxy)isoquinoline(114, 0.2 mmol, 1 equiv) in 5 mL of acetone was treated with mCPBA (113mg, 57%, 1.5 equiv) until HPLC showed complete reaction. Acetone wasevaporated, the residue was partitioned between methylene chloride andsaturated aqueous NaHCO₃. The organic layer was dried over MgSO₄ andused in the next step directly.

Step 3: The compound obtained in step 4 in 5 mL of pyridine was treatedwith tosyl chloride (46 mg, 1.2 equiv) at rt overnight and pyrine wasremoved under reduced pressure. The residue was reacted with 5 mL ofethanolamine for 12 h, and partitioned between methylene chloride andwater. The organic layer was dried over MgSO₄, filtered, evaporated andrefluxed in 3 mL of trifluoroacetic acid for 30 min. After removing TFA,the crude was purified by HPLC (C18 reversed phase) eluting with 0.5%TFA in H₂O/CH₃CN to give7-(2-(4-[(2-aminosulfonyl)phenyl]benzoylamino)-4-fluorophenoxy)1-aminoisoquinoline(77 mg, 50%). MS found for C₂₈H₂₂FN₄O₄S (M+H)⁺: 529.

Example 6007-(2-(4-[(2-aminosulfonyl)phenyl]benzoylamino)-4-trifluoromethylphenoxy)1-aminoisoquinoline

Step 1: A mixture of 7-(2-amino-4-trifluoromethylphenoxy)isoquinoline(305 mg, 1 mmol, 1.0 equiv), 4-[(2-t-butylaminosulfonyl)phenyl]benzoicacid (330 mg, 1 equiv), Bop reagent (880 mg, 2 equiv) and TEA (1.39 mL,10 equiv) in 3 mL of DMF was stirred at rt overnight. The mixture wasdiluted with EtOAc, washed with H₂O. The organic layer was dried overMgSO₄, filtered and evaporated. Flash chromatography on silica gel gave7-(2-(4-[(2-t-butylaminosulfonyl)phenyl]benzoylamino)-4-trifluoromethylphenoxy)isoquinoline(360 mg, 58%). MS found for C₃₃H₂₉F₃N₃O₄S (M+H)⁺: 620.

Step 2: A solution of7-(2-(4-[(2-t-butylaminosulfonyl)phenyl]benzoylamino)-4-trifluoromethylphenoxy)isoquinoline(124 mg, 0.2 mmol, 1 equiv) in 5 mL of acetone was treated with mCPBA(113 mg, 57%, 1.5 equiv) until HPLC showed complete reaction. Acetonewas evaporated, the residue was partitioned between methylene chlorideand saturated aqueous NaHCO₃. The organic layer was dried over MgSO₄ andused in the next step directly.

Step 3: The compound obtained in step 4 in 5 mL of pyridine was treatedwith tosyl chloride (46 mg, 1.2 equiv) at rt overnight and pyrine wasremoved under reduced pressure. The residue was reacted with 5 mL ofethanolamine for 12 h, and partitioned between methylene chloride andwater. The organic layer was dried over MgSO₄, filtered, evaporated andrefluxed in 3 mL of trifluoroacetic acid for 30 min. After removing TFA,the crude was purified by HPLC (C18 reversed phase) eluting with 0.5%TFA in H₂O/CH₃CN to give7-(2-(4-[(2-aminosulfonyl)phenyl]benzoylamino)-4-trifluoromethylphenoxy)1-aminoisoquinoline(64 mg, 52%). MS found for C₂₉H₂₂F₃N₄O₄S (M+H)⁺: 579.

Example 6017-(2-(4-[(2-aminosulfonyl)phenyl]benzoylamino)-4-methylsulfonylphenoxy)1-aminoisoquinoline

Step 1: A mixture of 7-(2-amino-4-methylsulfonylphenoxy)isoquinoline(315 mg, 1 mmol, 1.0 equiv), 4-[(2-t-butylaminosulfonyl)phenyl]benzoicacid (330 mg, 1 equiv), Bop reagent (880 mg, 2 equiv) and TEA (1.39 mL,10 equiv) in 3 mL of DMF was stirred at rt overnight. The mixture wasdiluted with EtOAc, washed with H₂O. The organic layer was dried overMgSO₄, filtered and evaporated. Flash chromatography on silica gel gave7-(2-(4-[(2-t-butylaminosulfonyl)phenyl]benzoylamino)-4-methlsulfonylphenoxy)isoquinoline(460 mg, 73%). MS found for C₃₃H₃₂N₃O₆S₂ (M+H)⁺: 630.

Step 2: A solution of7-(2-(4-[(2-t-butylaminosulfonyl)phenyl]benzoylamino)-4-methlsulfonylphenoxy)isoquinoline(126 mg, 0.2 mmol, 1 equiv) in 5 mL of acetone was treated with mCPBA(113 mg, 57%, 1.5 equiv) until HPLC showed complete reaction. Acetonewas evaporated, the residue was partitioned between methylene chlorideand saturated aqueous NaHCO₃. The organic layer was dried over MgSO₄ andused in the next step directly.

Step 3: The compound obtained in step 4 in 5 mL of pyridine was treatedwith tosyl chloride (46 mg, 1.2 equiv) at rt overnight and pyrine wasremoved under reduced pressure. The residue was reacted with 5 mL ofethanolamine for 12 h, and partitioned between methylene chloride andwater. The organic layer was dried over MgSO₄, filtered, evaporated andrefluxed in 3 mL of trifluoroacetic acid for 30 min. After removing TFA,the crude was purified by HPLC (C18 reversed phase) eluting with 0.5%TFA in H₂O/CH₃CN to give7-(2-(4-[(2-aminosulfonyl)phenyl]benzoylamino)-4-methylsulfonylphenoxy)1-aminoisoquinoline(94 mg, 80%). MS found for C₂₉H₂₅N₄O₆S₂ (M+H)⁺: 589.

Example 6023-(2-(4-[(2-aminosulfonyl)phenyl]phenylaminocarbonyl-4-nitrophenoxy)benzamidine

Step 1: A solution of 2-fluoro-5-nitrobenzoic acid (1.85 g, 10 mmol,1.33 equiv) in thionyl chloride (5 mL) was refluxed for 2 h andevaporated. The residue was redissolved in 20 mL of methylene chlorideand to the solution were added 4-[(2-t-butylaminosulfonyl)phenyl]aniline(2.0 g, 1.0 equiv) and 5 mL of pyridine. After stirring at rt overnight,the volatile was evaporated. Flash chromatography on silica gel1-(4-[(2-t-butylaminosulfonyl)phenyl]phenylaminocarbonyl)-2-fluoro-5-nitrobenzene(2.9 g, 99%). MS found for C₂₃H₂₃FN₃O₅S (M+H)⁺: 472.

Step 2: To a solution of1-(4-[(2-t-butylaminosulfonyl)phenyl]phenylaminocarbonyl)-2-fluoro-5-nitrobenzene(1.18 g, 0.25 mmol, 1.0 equiv) and 3-hydroxybenzonitrile (298 mg, 1.0equiv) in 10 mL of DMF was added K₂CO₃ (691 mg, 2 equiv). After stirringat 60° C. for 3 h, the mixture was diluted with EtOAc and washed withH₂O. The organic layer was dried over MgSO₄, filtered, evaporated andchromatographied to give3-(2-(4-[(2-t-butylaminosulfonyl)phenyl]phenylaminocarbonyl-4-nitrophenoxy)benzonitrile(950 g, 63%). MS found for C₃₀H₂₇N₄O₆S (M+H)⁺: 571.

Step 3: A stream of HCl(g) was bubbled through a 0° C. solution of3-(2-(4-[(2-t-butylaminosulfonyl)phenyl]phenylaminocarbonyl-4-nitrophenoxy)benzonitrile(57 mg, 0.1 mmol) in 5 mL of methanol until saturation. The mixture wasstirred at rt overnight and evaporated. The resulting residue wastreated with ammonium acetate (39 mg, 5 equiv) in 10 ml methanol atreflux temperature for 2 h. The solvent was removed at reduced pressureand the crude was purified by HPLC (C18 reversed phase) eluting with0.5% TFA in H₂O/CH₃CN to3-(2-(4-[(2-aminosulfonyl)phenyl]phenylaminocarbonyl-4-nitrophenoxy)benzamidine(24 mg, 45%). MS found for C₂₆H₂₂N₅O₆S (M+H)⁺: 532.

Example 6033-(2-(4-[(2-aminosulfonyl)phenyl]phenylaminocarbonyl-4-aminophenoxy)benzamidine

A mixture of3-(2-(4-[(2-aminosulfonyl)phenyl]phenylaminocarbonyl-4-nitrophenoxy)benzamidine(53 mg, 0.1 mmol, 1 equiv), 5 mL of 1N HCl, 5 mg of Pd/C (10%) in 10 mLof methanol was stirred at rt under 1 atm H₂ atomosphere overnight.After filtration through a thin layer of Celite and removal of thevolatile, the aqueous residue was purified by HPLC (C18 reversed phase)eluting with 0.5% TFA in H₂O/CH₃CN to3-(2-(4-[(2-aminosulfonyl)phenyl]phenylaminocarbonyl-4-aminophenoxy)benzamidine(31 mg, 66%). MS found for C₂₆H₂₄N₅O₄S (M+H)⁺: 502.

Example 6043-(2-(4-[(2-aminosulfonyl)phenyl]phenylaminocarbonyl-4-chlorophenoxy)benzamidine

Step 1: A mixture of3-(2-(4-[(2-t-butylaminosulfonyl)phenyl]phenylaminocarbonyl-4-nitrophenoxy)benzonitrile(570 mg, 1 mmol, 1 equiv) and SnCl₂.2H₂O (677 mg, 3 equiv) in 25 mL ofEtOAc was refluxed for 2 h. The reaction was quenched with sat. NaHCO₃.The organic layer was separated and dried over MgSO₄, filtered andevaporated to give3-(2-(4-[(2-t-butylaminosulfonyl)phenyl]phenylaminocarbonyl-4-aminophenoxy)benzonitrile(45 mg, 83%). MS found for C₃₀H₂₉N₄O₄S (M+H)⁺: 541.

Step 2: A mixture of t-BuNO₂ (21 mg, 0.1 mmol, 2 equiv), CuCl (20 mg, 2equiv) in 5 mL of acetonitrile was refluxed for 10 min. To the solutionwas added3-(2-(4-[(2-t-butylaminosulfonyl)phenyl]phenylaminocarbonyl-4-aminophenoxy)benzonitrile(54 mg, 0.1 mmol, 1 equiv). The mixture was refluxed for 1 h andevaporated. Flash chromatography with 1:2 EtOAc/hexane to give[(2-t-butylaminosulfonyl)phenyl]phenylaminocarbonyl-4-chlorophenoxy)benzonitrile(43 mg, 77%) MS found for C₃₀H₂₇ClN₃O₄S (M+H)⁺: 561.

Step 3: A stream of HCl(g) was bubbled through a 0° C. solution of3-(2-(4-[(2-t-butylaminosulfonyl)phenyl]phenylaminocarbonyl-4-chlorophenoxy)benzonitrile(56 mg, 0.1 mmol) in 5 mL of methanol until saturation. The mixture wasstirred at rt overnight and evaporated. The resulting residue wastreated with ammonium acetate (40 mg, 5 equiv) in 10 ml methanol atreflux temperature for 2 h. The solvent was removed at reduced pressureand the crude was purified by HPLC (C18 reversed phase) eluting with0.5% TFA in H₂O/CH₃CN to3-(2-(4-[(2-aminosulfonyl)phenyl]phenylaminocarbonyl-4-chlorophenoxy)benzamidine(47 mg, 84%). MS found for C₂₆H₂₂ClN₄O₄S (M+H)⁺: 521.

Example 6053-(2-(4-[(2-aminosulfonyl)phenyl]phenylaminocarbonyl-4-bromophenoxy)benzamidine

This compound was prepared according to the procedure described inexample 19. MS found for C₂₆H₂₂BrN₄O₄S (M+H)⁺: 565.

Example 6062-bromo-6-(2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenoxynaphthalene

A mixture of 2-bromo-6-(2-aminophenoxy)naphthalene (314 mg, 1 mmol, 1.0equiv), 4-[(2-t-butylaminosulfonyl)phenyl]benzoyl chloride (349 mg, 1equiv), pyridine (3 mL) in 10 mL of dichloromethane was stirred at rtovernight, washed with H₂O. The organic layer was dried over MgSO₄,filtered, evaporated and refluxed in 2 mL of trifluoroacetic acid for 30min. TFA was then evaporated and HPLC (C18 reversed phase) eluting with0.5% TFA in H₂O/CH₃CN gave2-bromo-6-(2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenoxynaphthalene (378 mg, 66%). MS found for C₂₉H₂₂BrN₂O₄S (M+H)⁺: 573.

Example 6073-methoxycarbonyl-2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenoxynaphthalene

A mixture of 3-methoxycarbonyl-2-(2-aminophenoxy) (294 mg, 1 mmol, 1.0equiv), 4-[(2-t-butylaminosulfonyl)phenyl]benzoyl chloride (349 mg, 1equiv), pyridine (3 mL) in 10 mL of dichloromethane was stirred at rtovernight, washed with H₂O. The organic layer was dried over MgSO₄,filtered, evaporated and refluxed in 2 mL of trifluoroacetic acid for 30min. TFA was then evaporated and HPLC (C18 reversed phase) eluting with0.5% TFA in H₂O/CH₃CN gave3-methoxycarbonyl-2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenoxynaphthalene (420 mg, 76%). MS found for C₃₁H₂₅N₂O₆S (M+H)⁺: 553.

Example 6083-hydroxycarbonyl-2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenoxynaphthalene

A solution of3-methoxycarbonyl-2-(4-methylsulfonyl-2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy)naphthalene(55 mg, 0.1 mmol, 1.0 equiv) in 5 mL of methanol was treated with 1NLiOH (2 mL) at rt for 2 h. Methanol was evaporated, the aqueous residuewas subjected to HPLC with 0.5% TFA in H₂O/CH₃CN to give3-hydroxycarbonyl-2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenoxynaphthalene (47 mg, 88%). MS found for C₃₀H₂₃N₂O₆S (M+H)⁺: 539.

Example 6093-aminocarbonyl-2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenoxynaphthalene

Step 1: A solution of3-methoxycarbonyl-2-(4-methylsulfonyl-2-(4-[(2-t-butylaminosulfonyl)phenyl]phenylcarbonylamino)phenoxy)naphthalene (40 mg, 0.066 mmol) in 5 mL of methanol was treated with 1NLiOH (2 mL) at rt for 2 h. Methanol was evaporated, and acidified with1N HCl until PH ˜1-2. The product (39 mg, 100%),3-hydroxycarbonyl-2-(4-methylsulfonyl-2-(4-[(2-t-butylaminosulfonyl)phenyl]phenylcarbonylamino)phenoxy)naphthalene,was extracted with EtOAc, dried over MgSO₄, filtered and evaporated. MSfound for C₃₄H₃₁N₂O₆S (M+H)⁺: 595.

Step 2: A solution of3-hydroxycarbonyl-2-(4-methylsulfonyl-2-(4-[(2-t-butylaminosulfonyl)phenyl]phenylcarbonylamino)phenoxy)naphthalene(39 mg, 0.066 mmol) was refluxed in 3 mL of thionyl chloride for 2 h andevaporated. The residue was then stirred in 5 mL of 2M ammonia inmethanol overnight. The volatile was evaporated and the residue wasrefluxed in 2 mL of trifluoroacetic acid overnight to give the product3-aminocarbonyl-2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenoxynaphthalene (14 mg, 39%) after HPLC (C18 reversed phase, eluting with0.5% TFA in H₂O/CH₃CN). MS found for C₃₀H₂₄N₃O₅S (M+H)⁺: 538.

Example 6103-methoxycarbonyl-2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy-6-bromonaphthalene

A mixture of 2-(2-aminophenoxy)-3-methoxycarbonyl-6-bromo naphthalene(372 mg, 1 mmol, 1.0 equiv), 4-[(2-t-butylaminosulfonyl)phenyl]benzoylchloride (349 mg, 1 equiv), pyridine (3 mL) in 10 mL of dichloromethanewas stirred at rt overnight, washed with H₂O. The organic layer wasdried over MgSO₄, filtered, evaporated and refluxed in 2 mL oftrifluoroacetic acid for 30 min. TFA was then evaporated and HPLC (C18reversed phase) eluting with 0.5% TFA in H₂O/CH₃CN gave3-methoxycarbonyl-2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy-6-bromonaphthalene (423 mg, 67%). MS found for C₃₁H₂₄BrN₂O₆S (M+H)⁺: 631.

Example 6113-hydroxycarbonyl-2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy-6-bromonaphthalene

A solution of3-methoxycarbonyl-2-(4-methylsulfonyl-2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy)-6-bromonaphthalene (63 mg, 0.1 mmol, 1.0 equiv) in 5 mL of methanol was treatedwith 1N LiOH (2 mL) at rt for 2 h. Methanol was evaporated, the aqueousresidue was subjected to HPLC with 0.5% TFA in H₂O/CH₃CN to give3-hydroxycarbonyl-2-(4-[(2-aminosulfonyl)phenyl]phenylcarbonylamino)phenoxy-6-bromonaphthalene (47 mg, 78%). MS found for C₃₀H₂₂BrN₂O₆S (M+H)⁺: 617.

Example 6123-(2-(4-[(2-aminosulfonyl)phenyl]-2-fluorophenylaminocarbonyl-4-aminophenoxy)benzamidine

This compound was prepared according to the procedure described inexample 17. MS found for MS found for C₂₆H₂₁FN₅O₆S (M+H)⁺: 550.

Example 6133-(2-(4-[(2-aminosulfonyl)phenyl]-2-fluorophenylaminocarbonyl-4-aminophenoxy)benzamidine

This compound was prepared according to the procedure described inexample 18. MS found for C₂₆H₂₃FN₅O₄S (M+H)⁺: 520.

Example 614

This compound was obtained as a side product in the preparation ofexample 18. MS (M+H)⁺: 530.

Example 615

Step 1: A mixture of3-(2-(4-[(2-t-butylaminosulfonyl)phenyl]phenylaminocarbonyl-4-nitrophenoxy)benzonitrile(1 equiv) and SnCl₂.2H₂O (3 equiv) in 15 mL of EtOAc was refluxed for 2h. The mixture was diluted with EtOAc and washed with saturated aqueousNaHCO3. The organic layer was dried over Na2SO4, filtered andevaporated.

Step 2: The product obtained in step 1 (1 equiv) in 2 mL of pyridine wastreated with AcCl (1 equiv) over night. The mixture was diluted withmethylene chloride and washed with water. The organic layer was driedover Na₂SO₄, filtered and evaporated.

Step 3: A stream of HCl(g) was bubbled through a 0° C. solution of theproduct obtained in step 2 (1 equiv) in 5 mL of methanol untilsaturation. The mixture was stirred at rt overnight and evaporated. Theresulting residue was treated with ammonium (5 equiv) in 10 mL ofmethanol at reflux temperature for 2 h. The solvent was removed atreduced pressure and the crude was purified by HPLC (C18 reversed phase)eluting with 0.5% TFA in H₂O/CH₃CN to the title product. MS (M+H)⁺: 544.

Example 616

This compound was similarly made as example 30. MS (M+H)⁺: 580.

Examples 617-624

The following compounds were made according to the methods previouslydescribed.

Example 625

A mixture of compound 20 (1 equiv), 5 mL of 1N HCl, 5 mg of Pd/C (10%)in 10 mL of methanol was stirred at rt under 1 atm H₂ atomosphereovernight. After filtration through a thin layer of Celite and removalof the volatile, the aqueous residue was purified by HPLC (C18 reversedphase) eluting with 0.5% TFA in H₂O/CH₃CN to give the title compound. MS(M+H)⁺: 487.

Examples 626-631

The following compounds were prepared according to the proceduredescribed in the formation of amidines except that NH₂OH was usedinstead of NH₄OAc.

Example 6323-(2-(4-[(2-aminosulfonyl)phenyl]benzoylamino)phenoxy)benzylamine

A mixture of3-(2-(4-[(2-t-butylaminosulfonyl)phenyl]benzoylamino)phenoxy)benzonitrile(25 mg), 5 mL of 1N HCl, 5 mg of Pd/C (10%) in 10 mL of methanol wasstirred at rt under 1 atm H₂ atomosphere overnight. After filtrationthrough a thin layer of Celite and removal of the volatile, the aqueousresidue was dried on vacuum pump and then refluxed with 1 mL of TFA for2 h, evaporated and purified by HPLC (C18 reversed phase) eluting with0.5% TFA in H₂O/CH₃CN to give the title compound. MS (M+H)⁺: 500.

Example 6333-[(3-{[4-(2-sulfamoylphenyl)phenyl]carbonylamino}-2-thienyl)carbonylamino]benzenecarboxamidine

Step 1: A mixture of 3-amino-2-((3-cyanophenyl)aminocarbonyl)thiophene(1 equiv), 4-[(2-t-butylaminosulfonyl)phenyl]benzoyl chloride (1 equiv),pyridine (5 equiv) in 15 mL of dichloromethane was stirred at rtovernight. The mixture was diluted with methylene chloride, washed withH₂O. The organic layer was dried over MgSO₄, filtered and evaporated.

Step 2: A stream of HCl(g) was bubbled through a 0° C. solution of thecompound obtained in step 1 in 5 mL of methanol until saturation. Themixture was stirred at rt overnight and evaporated. The resultingresidue was treated with ammonium acetate (5 equiv) in 10 mL of methanolat reflux temperature for 2 h. The solvent was evaporated and the crudebenzamidine was purified by HPLC (C18 reversed phase) eluting with 0.5%TFA in H₂O/CH₃CN to give the title compound. ES-MS 520 (M+1).

Example 6343-[(3-{[4-(2-sulfamoylphenyl)phenyl]carbonylamino}-2-thienyl)carbonylamino]benzenecarboxamidine

Step 1: A mixture of 2-nitroaniline, 3-cyanobenzoyl chloride (1 equiv),pyridine (5 equiv) in 15 mL of dichloromethane was stirred at rtovernight. The mixture was diluted with methylene chloride, washed withH₂O. The organic layer was dried over MgSO₄, filtered and evaporated.

Step 2: A mixture of the compound obtained in step 1 (1 equiv) andSnCl₂.2H₂O (3 equiv) in 15 mL of EtOAc was refluxed for 2 h. The mixturewas diluted with EtOAc and washed with saturated aqueous NaHCO₃. Theorganic layer was dried over Na₂SO₄, filtered and evaporated.

Step 3: A mixture of the compound obtained in step 2 (1 equiv),4-[(2-t-butylaminosulfonyl)phenyl]benzoyl chloride (1 equiv), pyridine(5 equiv) in 15 mL of dichloromethane was stirred at rt overnight. Themixture was diluted with methylene chloride, washed with H₂O. Theorganic layer was dried over MgSO₄, filtered and evaporated.

Step 4: A stream of HCl(g) was bubbled through a 0° C. solution of thecompound obtained in step 1 in 5 mL of methanol until saturation. Themixture was stirred at rt overnight and evaporated. The resultingresidue was treated with ammonium acetate (5 equiv) in 10 mL of methanolat reflux temperature for 2 h. The solvent was evaporated and the crudebenzamidine was purified by HPLC (C18 reversed phase) eluting with 0.5%TFA in H₂O/CH₃CN to give the title compound. ES-MS 494 (M+1).

Example 635-640

The following compounds were prepared according to the procedurepreviously described.

Example 641

This compound was obtained as a side product in the preparation ofExample 322, described earlier, above. ES-MS 530 (M+H).

The above description and illustrative examples show numerous compoundswithin the formula A-Q-D-E-G-J-X which are potent factor Xa inhibitors.The description and illustrative examples also show the variety ofcombinations and substituents for each group A, Q, D, E, G, J and Xwhich may be prepared according to the invention and be useful as factorXa inhibitors. While, for example, compounds having the same A-Qstructure but a variety of substituents or D-E-G and/or J-X structuresand their substituents are described and shown, the description andillustrative examples are intended to show that compounds of theinvention having a different A-Q structure can also have variouscombinations of D-E-G- and/or J-X structures, even though such compoundsmay not be illustrated in the examples. In other words, each groupwithin the A-Q-D-E-G-J-X, as each is defined above with theirsubstituents, may be varied and combined to form sub-genuses andcompounds of the invention. The description and illustrative examplesshow such combinations and are not intended to limit the sub-genuses orcompounds within the A-Q-D-E-G-J-X genus of the invention.

Without further description, it is believed that one of ordinary skillin the art can, using the preceding description and the illustrativeexamples, make and utilize the compounds of the present invention andpractice the claimed methods. It should be understood that the foregoingdiscussion and examples merely present a detailed description of certainpreferred embodiments. It will be apparent to those of ordinary skill inthe art that various modifications and equivalents can be made withoutdeparting from the spirit and scope of the invention. All the patents,journal articles and other documents discussed or cited above are hereinincorporated by reference.

1-83. (canceled)
 84. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the formula

or a pharmaceutically acceptable salt thereof and a therapeutic agent.
 85. The composition of claim 84, wherein the salt is the maleate salt.
 86. The composition of claim 84, wherein the therapeutic agent is selected from the group consisting of an anticoagulant agent, a thrombolytic agent, and an antithrombotic.
 87. The composition of claim 84, wherein the therapeutic agent is selected from the group consisting of an urokinase, prourokinase, streptokinase, heparin, aspirin, and warfarin.
 88. The composition of claim 84, wherein the therapeutic agent is aspirin.
 89. A method for preventing or treating a condition in a mammal in need thereof characterized by undesired thrombosis comprising administering to said mammal a therapeutically effective amount of a compound of the formula

or a pharmaceutically acceptable salt thereof and aspirin.
 90. The method of claim 89, wherein the condition is selected from the group consisting of acute coronary syndrome, myocardial infarction, unstable angina, refractory angina, occlusive coronary thrombus, occurring post-thrombolytic therapy or post-coronary angioplasty, cerebrovascular syndrome, embolic stroke, thrombotic stroke or transient ischemic attacks, venous thrombosis, pulmonary embolus, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, thromboangiitis obliterans, thrombotic disease associated with heparin induced thrombocytopenia, thrombotic complications associated with extracorporeal circulation, thrombotic complications associated with instrumentation, and thrombotic complications associated with the fitting of prosthetic devices.
 91. The method of claim 89, wherein the salt is administered in a pharmaceutical composition comprising the salt and a pharmaceutically acceptable carrier.
 92. The method of claim 91, wherein the salt is the maleate salt. 